Quinoline compounds, intermediates, preparation methods and uses thereof

ABSTRACT

A kind of quinoline compounds as formula A, pharmaceutical accepted solvates, optical isomers or polymorphisms thereof. The intermediates of formula D. in which, R1, R2 and R3 is independently H, halo or the subustitents of formula H, in which, R is H, halo, C1˜C4alkyl, C1˜C4alkoxyl. The preparation methods and the uses for the manufacture of a medicament of inhibiting the HMG CoA reductase and treating the diseases relating to the high blood fat. Compared with the fluvastatin, rosuvatatin, pitavastatin disclosed in the prior arts, present quinoline compounds have better activity of inhibiting HMG CoA reductase. Present quinoline compounds can be used for treating the diseases relating to the high blood fat.

FIELD OF THE TECHNOLOGY

The present invention pertains to the art of synthesis technology in medicinal chemistry. More particularly, this invention is related to novel quinoline compounds and their intermediates, preparation methods and applications in pharmaceutical field.

BACKGROUND

Hypocholesterolemic agents have evolved rapidly when hypercholesterolemia is well recognized as a primary risk factor in atherosclerotic diseases and coronary heart diseases. A class of drugs, such as 3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA reductase) inhibitors, the statins, are currently potent hypocholesterolemic agents. (Cai Z-Y, Zhou W—C. Progresses in researches of HMG CoA reductase inhibitors, Chinese Journal of New Drugs, 2006, 15 (22): 1907-1911). The launched drugs, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, and pitavastatin are currently available hypocholesterolemic agents. However, as far as human requirement is concerned, there is a need to develop new potent hypocholesterolemic drugs.

The structure of the fully synthetic statins is characterized by desmethylmevalonic acid or the lactone, the pharmacophore which is connected to a lipophilic ring, such as hexahydronaphthalene, indole, pyrrole, pyrimidine, or quinoline. Systematical QSAR study on quinoline statin compounds, such as pitavastatin, show desmethylmevalonic acid linked through a trans-ethylene group to position 3 in quinoline exhibited good activity in inhibiting HMG CoA reductase. The introduction of chloro, methyl or methoxy etc. to the 6-, 7- or 8-position of the quinoline nucleus may increase the inhibitory potency. (Cai Z-Y, Zhou W-C. Progresses in researches of HMG CoA reductase inhibitors, Chinese Journal of New Drugs, 2006, 15 (22): 1907-1911). So far in the known quinolines as HMG CoA inhibitors, the aryl group such as 4-fluorophenyl, is directly linked to position 4 in quinoline, the derivatives from 4-thiohenyl have not been reported.

DETAILED DESCRIPTION OF THE INVENTION

An object of the present invention is directed to a novel quinoline compound of the formula A, and its pharmaceutically acceptable solvate, stereoisomers or polymorphism that provide the HMG CoA reductase inhibition activities and that can be used as hypocholesterolemic agents.

The quinoline compound of the formula A in this present invention is designed with pitavastatin as a leading compound. The pharmacophore moiety, desmethylmevalonic lactone, is connected to position 3 in the quinoline nucleus, and the nucleus is flanked at position 4 by substituted thiophenyl as a lipophilic group, and at position 6, 7, 8 by different group, such as substituted thiophenyl or halogen.

Wherein

R₁, R₂ and R₃ are each independently selected from the group consisting of hydrogen, halogen, the group shown in formula H,

Wherein

R is selected from the group consisting of hydrogen, halogen, C1˜4 alkyl or C1˜4 alkoxy.

The halogen in this invention is selected from the elements consisting of F, Cl, Br or I, and more preferred element is F or Cl. R is selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy or isopropoxy.

In another preferred embodiment, the quinoline compound in this invention may be selected from the following:

-   (4R,6S)-6-[(E)-2-(6,7,8-trifluoro-4-(4-isopropylthiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one; -   (4R,6S)-6-[(E)-2-(6-fluoro-4,7-di-(3-methoxythiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one; -   (4R,6S)-6-[(E)-2-(4,     6,7,8-tetra-(3-methoxythiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one; -   (4R,6S)-6-[(E)-2-(6-fluoro-4,7-di-(thiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one; -   (4R,6S)-6-[(E)-2-(6,7,8-trifluoro-4-(4-fluorothiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one; -   (4R,6S)-6-[(E)-2-(7-chloro-6-fluoro-4-(3-methoxythiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one; -   (4R,6S)-6-[(E)-2-(6-fluoro-4,7-di-(4-isopropylthiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one; -   (4R,6S)-6-[(E)-2-(6,7,8-trifluoro-4-thiophenylquinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one; -   (4R,6S)-6-[(E)-2-(6-fluoro-4,7,8-tri-(4-fluorothiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one     Or -   (4R,6S)-6-[(E)-2-(4-(4-isopropylthiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one.

The pharmaceutically acceptable solvate in this invention is the hydrate, and solvate with C1˜4 alcohol or other organic solvents.

Another object of the present invention is directed to the intermediate of the formula D.

Wherein R₁, R₂ and R₃ are each independently selected from the group consisting of hydrogen, halogen, the group shown in formula H,

Wherein

R is selected from the group consisting of hydrogen, halogen, C1˜4 alkyl or C1˜4 alkoxy.

The halogen in this invention is selected from the element consisting of F, Cl, Br or I, and more preferred element is F or Cl. R is selected from the group consisting of methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy or isopropoxy.

A further object of the present invention is directed to the preparation of intermediate of the formula D, which is comprising that compound B is reacted with compound C, tert-butyl

(3R,5S)-6-oxo-3,5-dihydroxy-3,5-O-isopropylidene-hexanoate, by Wittig-Horner reaction under basic condition in organic solvent.

Wherein

R₁, R₂ and R₃ are each independently selected from the group consisting of hydrogen, halogen, the group shown in formula H,

Wherein

R is selected from the group consisting of hydrogen, halogen, C1˜4 alkyl or C1˜4 alkoxy.

The compound Bis prepared by the method shown in below:

Wherein R₁, R₂, R₃ and R are defined as the above. R₄, R₅ and R₆ are each independently selected from the group consisting of hydrogen or halogen.

The novel quinoline compound A is synthesized in optically pure forms by the general method as follows:

1. Chlorination and Aromatic Nucleophilic Substitution

The monosubstituted or multisubstituted compounds of formula E are prepared with ethyl 4-hydroxy-6,7,8-trisubstituted-quinoline-3-carboxylates as the starting materials by chlorination with POCl₃ and aromatic nucleophilic substitution under basic condition. The solvent in aromatic nucleophilic substitution is THF, EtOAc, toluene, DMF, or DMSO etc. The nucleophiles are the corresponding thiophenols. The base used in the reaction is selected from Et₃ N, pyridine, Na₂CO₃, K₂CO₃, NaOH, NaH, and n-BuLi etc. The temperature of reaction is −30° C.˜150° C. The 4-monosubstituted, 4,7-disubstituted, 4,7,8-trisubstituted or 4,6,7,8-tetrasubstituted compound of formula E is highly regiospecifically prepared under different condition, such as different substrate, different mol ratio of substrate and nucleophilic agents, base, solvent and reaction temperature. Characterizations of compounds E are shown in Tables 31-40.

2. Reduction

Compound F is prepared from compound E by reducing agents via reduction under organic solvent. The organic solvent is selected from benzene, toluene, THF, methanol, ethanol etc. The organic solvent is also selected from the mixture of two solvents mentioned above. The reducing agent is selected from diisobutylaluminum hydride (DIBAL-H), KBH₄/ZnCl₂, LiAlH₄, LiAlH₄/LiCl, NaBH₄, NaBH₄/LiCl etc. The preferred organic solvent is toluene. The optimal reducing agent is diisobutylaluminum hydride (DIBAL-H). The optimal reaction temperature is 0° C.˜20° C. Characterizations of compounds F are shown in Tables 41-50.

3. Bromination:

Bromination of the compound F with PBr₃ affords the bromide G. The solvent for the reaction is selected from THF, t-BuOMe, CH₂Cl₂, CHCl₃, toluene etc, and the optimal solvent is CH₂Cl₂. The reaction temperature is 0° C.˜100° C., and the optimal reaction temperature is 0° C.˜30° C.

4. Phosphorylation:

The compound G is converted to the corresponding phosphorus compound B with Ph₂POEt. The solvent is selected from THF, t-BuOMe, CH₂Cl₂, CHCl₃, toluene etc, and the preferred solvent is toluene. The reaction temperature is 20□˜150□, and the optimal reaction temperature is 100° C.˜120° C. Characterizations of compound G and B are shown in Tables 51˜60.

Wittig-Hornor reaction in this invention is the widely-known technology. The details of the Wittig-Hornor reaction in this invention are as follows: compound B is reacted with compound C, tert-butyl (3R,5S)-6-oxo-3,5-dihydroxy-3,5-O-isopropylidene-hexanoate under basic condition in organic solvent.

The solvent is selected from THF, Et₂O, t-BuOMe, toluene etc., and the optimal solvent is THF. The alkaline is selected from lithium 2,2,6,6-tetramethylpiperidine, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, lithium n-butyl, NaH etc, and the optimal alkaline is lithium 2,2,6,6-tetramethylpiperidine.

The preferred conditions for the Wittig-Hornor reaction is that the optimal reaction temperature is −100° C.˜50° C., and preferably between −78° C. and 25° C. The optimal reaction time was 20˜48 hours. The mol ratio of compound B, compound C and alkaline is 1:1:1˜1:2:4, and more preferred is 1:1.2:1.5. Characterizations of compound D are shown in Tables 1˜10.

Another object of the present invention is directed to the preparation of quinoline compound. The compound D is deprotected and lactonized with acid in solvent to give the target compounds A. The acid is selected from CH₃COOH, CF₃COOH or HCl, and more preferred is CF₃COOH. The volume percentage of the acid in solvent is 5˜40%, and more preferred is 20%. The optimal reaction temperature is 0° C.˜80° C., and more preferred is 25° C. The optimal reaction time is 1˜8 hours. The solvent is selected from one or more of THF, t-BuOMe, CH₂Cl₂, CHCl₃, toluene etc., and more preferred is CH₂Cl₂. Characterizations of compound D are shown in Tables 11˜30.

Yet another object of the present invention is directed to the quinoline compound, and its pharmaceutically acceptable solvate, stereoisomers or polymorphism which is prepared for inhibition of HMG CoA reductase and useful in the treatment of the hypercholesterolemic.

The present invention provides pharmaceutical compositions which comprise quinoline compound A and any other pharmaceutically acceptable carriers. The carriers include conventional drug carries in the pharmaceutical art, for instance, diluents or excipients such as water; binders such as cellulose derivatives, gelatin or polyvinylpyrrolidone, etc; fillers such as starch; disintegrants such as calcium carbonate or sodium bicarbonate. Additionally, other excipients such as essence and/or sweetener can be included.

A variety of dosage forms can be prepared with the pharmaceutical compositions comprising quinoline compound A of the invention as active ingredients by conventional methods in the medical field. The solid dosage forms such as tablets, powders or capsules can be prepared for oral usage. The injection is prepared for injection usage. The content of the compound A of the present invention in the formulation is 0.1%˜99.9% (w/w), and more preferred is 0.5˜90% (w/w).

The dosage forms comprising quinoline compound A of the invention as active ingredients may be prepared for intravenous injection, subcutaneous injection or oral usage, which can be administered to patients who need such therapy. The conventional dose is 1˜100 mg/kg/day, according to the disease and patients' age.

The advantages of this invention are that: as compared with the drugs known in the art, such as fluvastatin, rosuvastatin or pitavastatin, the quinoline compound A of the present invention is provided with more potent in inhibiting HMG CoA reductase which can be used to treat the related disease of hypercholesterolemic.

EMBODIMENTS OF THE INVENTION

Other features of the invention will become apparent in the course of the following description of exemplary embodiments which are given for illustration of this invention and are not intended to be limiting thereof.

Preparation Example 1 Ethyl 4-chloro-6,7,8-trifluoroquinoline 3-carboxylate

A solution of ethyl 4-hydroxy-6,7,8-trifluoroquinoline-3-carboxylate (59.0 g) and POCl₃ (500 ml) was refluxed for 8 h. Excess POCl₃ was distilled off, the residue was removed into the mixture of ice and water. Solid NaHCO₃ was added into the mixture to pH 7˜8 and the precipitated solid was isolated by filtration. The crude was recrystallized by toluene to afford the title compound (41.3 g, 65.6% yield), mp: 110-112° C.

ethyl 4-chloro-quinoline-3-carboxylate, ethyl 6-fluoro-4,7-dichloroquinoline-3-carboxylate, and ethyl 4,7-dichloro-quinoline-3-carboxylate, were prepared in the manner analogous to the method described above, when ethyl 4-hydroxy-quinoline-3-carboxylate, ethyl 4-hydroxy-6-fluoro-7-chloro-quinoline-3-carboxylate, and ethyl 4-hydroxy-7-chloro-quinoline-3-carboxylate were used as the starting material respectively.

Preparation Example 2 Ethyl 4-substituted thiophenyl-quinoline-3-carboxylate (E1˜4)

A mixture of ethyl 4-chloro-quinoline-3-carboxylate (8.0 g, 34 mmol), 4-fluoro thiophenol (5.2 g, 41 mmol) and triethylamine (6.9 g, 68 mmol) in THF (80 mL) was stirred at room temperature for 30 min. The insoluble material was filtered off. The filtrate was concentrated, and the residue was recrystallized with toluene/petroleum ether to afford ethyl 4-(4-fluoro-thiophenyl-quinoline-3-carboxylate (10.0 g, E2). Ethyl 4-thiophenyl-quinoline-3-carboxylate (E1), ethyl 4-(3-methoxy-thiophenyl-quinoline-3-carboxylate (E3), and ethyl 4-(4-isopropyl-thiophenyl-quinoline-3-carboxylate (E4), were prepared in the manner analogous to the method described above, when 4-fluoro-thiophenol was replaced with thiophenol, 3-methoxy-thiophenol, and 4-isopropyl-thiophenol respectively. The data of yield, melting points (Mp.) and ¹H-NMR spectra of compound E1-4 was shown in Table 1.

Preparation Example 3 Ethyl 7-chloro-4-substituted thiophenyl-quinoline-3-carboxylate (E5˜8)

Compounds of E5˜8 were prepared in the manner analogous to the method of Preparation example 2, when ethyl 4,7-dichloro-quinoline-3-carboxylate was reacted with thiophenol, 4-fluoro-thiophenol, 3-methoxy-thiophenol, and 4-isopropyl-thiophenol respectively. The data of yield, melting points (Mp.) and ¹H-NMR spectra of compound E5-8 was shown in Table 2.

Preparation Example 4 Ethyl 6-fluoro-7-chloro-4-substituted thiophenyl-quinoline-3-carboxylate (E9˜12)

Compounds of E9˜12 were prepared in the manner analogous to the method of Preparation example 2, when ethyl 6-fluoro-4,7-dichloro-quinoline-3-carboxylate was reacted with thiophenol, 4-fluoro-thiophenol, 3-methoxy-thiophenol, and 4-isopropyl-thiophenol respectively. The data of yield, melting points (Mp.) and ¹H-NMR spectra of compound E9˜12 was shown in Table 3.

Preparation Example 5 Ethyl 6,7,8-trifluoro-4-substituted thiophenyl-quinoline-3-carboxylate (E13˜16)

A solution of triethylamine (0.9 g, 8.6 mmol) in THF (60 ml) was dropped into a mixture of ethyl 4-chloro-6,7,8-trifluoro-quinoline-3-carboxylate (5.0 g, 17.3 mmol), and 4-fluoro-thiophenol (2.2 g, 17.3 mmol) in THF (50 ml) at −15° C. The mixture was stirred for 1 h at this temperature before quenching with water and ethyl acetate. The organic layer was separated, washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by flash chromatography (silica gel, petroleum ether-EtOAc, 10:1) to provide the title compound as a yellow solid, E14, (4.0 g, 60.0%). mp: 126-8° C.

Compounds E13, E15, and E16 were prepared in the manner similar to the method described above, when 4-fluoro-thiophenol was replaced with thiophenol, 3-methoxy-thiophenol, and 4-isopropyl-thiophenol respectively. The data of yield, melting points (Mp.) and ¹H-NMR spectra of compound E13˜16 was shown in Table 4.

Preparation Example 6 Ethyl 4,7-disubstituted-thiophenyl-quinoline-3-carboxylate (E17˜20)

3-Methoxythiophenol (10.8 g, 77 mmol) was added to a mixture of NaH (60%, 3.0 g, 75 mmol) in DMF (30 ml) at 0° C. The resulting mixture was stirred at 0° C. for 0.5 h and then 4,7-dichloro-quinoline-3-carboxylate (7.0 g, 25.9 mmol) was added. The mixture was stirred at 60° C. for 0.5 h. The reaction mixture was transferred to a separatory funnel. Ethyl acetate and water were added. The organic layer was separated, washed with brine, dried over Na₂SO₄, and concentrated. The resulting oil was purified by silica gel chromatography (petroleum ether-EtOAc, 6:1) to provide the title compound, E19, (10.9 g, 88.1%) as an oil.

Compounds E17, E18, and E20 were prepared in the manner similar to the method described above, when 3-methoxy-thiophenol was replaced with thiophenol, 4-fluoro-thiophenol, and 4-isopropyl-thiophenol respectively. The data of yield, melting points (Mp.) and ¹H-NMR spectra of compound E17˜20 were shown in Table 5.

Preparation Example 7 Ethyl 6-fluoro 4,7-disubstituted-thiophenyl-quinoline-3-carboxylate (E21˜24)

A mixture of ethyl 6-fluoro 4,7-dichloro-quinoline-3-carboxylate (6.0 g, 20.8 mmol), 3-methoxy-thiophenol (5.8 g, 41.6 mmol) in DMF (20 ml) was stirred at room temperature for 0.5 hour and then cooled to 0° C. Anhydrous K₂CO₃ (20.0 g, 145 mmol) was added into the mixture and stirred for 1 hour below 10° C. The solid was isolated by filtration and washed with EtOAc. The filtrate was transferred to a separatory funnel, and ethyl acetate and water were added. The organic layer was separated, washed with brine, dried over Na₂SO₄, and concentrated. The resulting oil was purified by silica gel chromatography (petroleum ether-EtOAc, 6:1) to provide the title compound, E23, (6.2 g, 60.0%) as oil.

Compounds E21, E22, and E24 were prepared in the manner analogous to the method described above, when 3-methoxy-thiophenol was replaced with thiophenol, 4-fluoro-thiophenol, and 4-isopropyl-thiophenol respectively. The data of yield, melting points (Mp.) and ¹H-NMR spectra of compound E21˜24 were shown in Table 6.

Preparation Example 8 Ethyl 6,8-difluoro-4,7-disubstituted-thiophenyl-quinoline-3-carboxylate (E25˜28)

About 7.7 ml Et₃N was added to a solution of ethyl 6,7,8-trifluoro-4-chloro-quinoline-3-carboxylate (8.0 g, 27.4 mmol) and 4-isopropylthiophenol (8.4 g, 55 mmol) in THF (80 ml) at room temperature and stirred for 1 hour. The insoluble materials were filtered off, and the filtrate was evaporated in vacuum to give the crude product. Recrystallization from petroleum ether gave the compound, E28, as a yellow solid (7.4 g, 50.0%), mp: 75-77° C.

Compounds E25, E26, and E27 were prepared in the manner analogous to the method described above, when 4-isopropyl-thiophenol was replaced with thiophenol, 4-fluoro-thiophenol, and 3-methoxy-thiophenol respectively. The data of yield, melting points (Mp.) and ¹H-NMR spectra of compound E25˜28 were shown in Table 7.

Preparation Example 9 Ethyl 4,6,7-trisubstituted-thiophenyl-quinoline-3-carboxylate (E29˜32)

Ethyl 6-fluoro-4,7-dichloro-quinoline-3-carboxylate (7.1 g, 27.4 mmol) and 4-isopropyl-thiophenol (13.7 g, 90.1 mmol) were suspended in DMF (80 ml). The mixture was heated to 60° C. and stirred until the material was dissolved. Cooled to 25° C. and added to anhydrous K₂CO₃ (37.8 g, 274 mmol), the mixture was stirred for 1 h at 25° C. The insoluble materials were filtered off, and the filtrate was transferred to a separatory funnel, and ethyl acetate and water were added. The organic layer was separated, washed with brine, dried over Na₂SO₄, and concentrated to dryness. The resulting oil was purified by silica gel chromatography (petroleum ether-EtOAc, 6:1) to provide the compound, E32, (14.9 g, 83.5%) as oil.

Compounds E29, E30, and E31 were prepared in the manner analogous to the method described above, when 4-isopropylthiophenol was replaced with thiophenol, 4-fluoro-thiophenol, and 3-methoxy-thiophenol respectively. The data of yield, melting points (Mp.) and ¹H-NMR spectra of compound E29˜32 were shown in Table 8.

Preparation Example 10 Ethyl 6-fluoro-4,7,8-trisubstituted-thiophenyl-quinoline-3-carboxylate (E33˜36)

Anhydrous K₂CO₃ (37.8 g, 274 mmol) was added to a mixture of ethyl 6,7,8-trifluoro-4-chloro-quinoline-3-carboxylate (8.0 g, 27.4 mmol) and 4-isopropyl-thiophenol (13.7 g, 90.1 mmol) in DMF (80 ml) at 25° C. and stirred for 1 h. The insoluble materials were filtered off, and the filtrate was transferred to a separatory funnel, and ethyl acetate and water were added. The organic layer was separated, washed with brine, dried over Na₂SO₄, and concentrated to dryness. The resulting oil was purified by silica gel chromatography (petroleum ether-EtOAc, 6:1) to provide the compound, E36, (13.0 g, 65.8%) as oil.

Compounds E33, E34, and E35 were prepared in the manner analogous to the method described above, when 4-isopropylthiophenol was replaced with thiophenol, 4-fluoro-thiophenol, and 3-methoxy-thiophenol respectively. The data of yield, melting points (Mp.) and ¹H-NMR spectra of compound E33˜36 were shown in Table 9.

Preparation Example 11 Ethyl 4,6,7,8-tetrasubstituted-thiophenyl-quinoline-3-carboxylate (E37˜40)

A mixture of ethyl 6,7,8-trifluoro-4-chloro-quinoline-3-carboxylate (8.0 g, 27.4 mmol), 4-isopropyl-thiophenol (18.7 g, 123.3 mmol), anhydrous K₂CO₃ (37.8 g, 274 mmol) in DMF (80 ml) was stirred at 60° C. for 1 hour. The insoluble materials were filtered off, and the filtrate was transferred to a separatory funnel and ethyl acetate and water were added. The organic layer was separated, washed with brine, dried over Na₂SO₄, and concentrated to dryness. The resulting oil was purified by silica gel chromatography (petroleum ether-EtOAc, 6:1) to provide the title compound, E40, (19.4 g, 84.3%) as oil.

Compounds E37, E38, and E39 were prepared in the manner analogous to the method described above, when 4-isopropylthiophenol was replaced with thiophenol, 4-fluoro-thiophenol, and 3-methoxy-thiophenol respectively. The data of yield, melting points (Mp.) and ¹H-NMR spectra of compound E37˜40 was shown in Table 10.

Preparation Example 12 4-Thiophenyl-quinoline-3-methanol (F1)

A suspension of LiAlH₄ (1.0 g, 29.4 mmol) and anhydrous LiCl (1.2 g, 29.4 mmol) in anhydrous THF (30 ml) was stirred for 0.5 h under an atmosphere of nitrogen at 00° C. The solution of E1 (3.2 g, 9.8 mmol) in anhydrous THF (10 ml) was added into the resulting suspension at 0° C. and stirred for 2 h before adding Na₂SO₄.10H₂O slowly. The insolubable material was filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatography (petroleum ether-EtOAc, 2:1) to provide the title compound (0.28 g, 10%).

Preparation Example 13 4-(4-Fluoro-thiophenyl) quinoline-3-methanol (F2)

A mixture of anhydrous ZnCl₂ (2.9 g, 21.4 mmol) and KBH₄ (2.3 g, 42.8 mmol) in THF (15 ml) was stirred at room temperature for 2 h. A solution of E2 (3.5 g, 10.7 mmol) in toluene (75 ml) was added and refluxed (95° C.) overnight. The reaction mixture was cooled to room temperature, the insoluble was filtered off, and the filter cake was washed with hot toluene. All the toluene was combined and washed with water, 0.1 mol/L NaOH, brine, dried over Na₂SO₄, and concentrated to dryness. The resulting oil was purified by silica gel chromatography (petroleum ether-EtOAc, 1:1) to provide the title compound F2 (0.3 g, 9.8%).

Preparation Example 14 4-(3-methoxy-thiophenyl)quinoline-3-methanol (F2)

NaBH₄ (1.2 g, 31.7 mmol) was added into a solution of E3 (5.0 g, 15.3 mmol) in EtOH (100 ml) at room temperature and stirred for 8 h. The insoluble material was filtered and the filtrate was concentrated to dryness. The residue was purified by silica gel chromatography (petroleum ether-EtOAc, 1:1.5) to provide the title compound F3 (1.3 g, 30%).

Preparation Example 15 7-Chloro-4-(4-fluoro-thiophenyl)quinoline-3-methanol (F6)

Anhydrous LiCl (0.14 g, 3.3 mmol) was added into a solution of E6 (1.0 g, 2.6 mmol) in EtOH (15 ml) and stirred for 5 min. at 0° C. NaBH₄ (0.13 g, 3.4 mmol) was added into the resulting mixture and stirred for 0.5 h at 0° C. The reaction mixture was stirred for 18 h at room temperature before concentration to dryness. Water and EtOAc was added to the residue and the organic layer was separated, washed with brine, dried over Na₂SO₄ and concentrated. The residue was purified by silica gel chromatography (petroleum ether-EtOAc, 1:1) to provide the title compound F6 (0.27 g, 30%).

Preparation Example 16 6,7,8-trifluoro-4-thiophenyl-quinoline-3-methanol (F13)

About 22 ml (55 mmol) of a 2.5 mol/L DIBAL-H in toluene was added to a solution of E13 (8.0 g, 21.9 mmol) in anhydrous toluene (80 ml) at 0° C. under an atmosphere of nitrogen. The resulting solution was stirred for 2 h at 00° C. before quenching with 6 mol/L HCl. The mixture was added to EtOAc and the organic layer was separated, washed with water, dried over Na₂SO₄ and concentration. Recrystallization from 95% ethanol to give the title compound as a solid (5.0 g, 70.6%), mp: 126˜128° C.

Preparation Example 17 Preparation of compounds F1˜40

Compounds, F1˜40, were prepared in the manner similar to the method of Preparation example 16, when Compounds E1˜40 were used as the material respectively. The data of yield, melting points (Mp.) and ¹H-NMR spectra of compounds F1˜40 were shown in Table 11˜20.

Preparation Example 18 6,7,8-Trifluoro-4-thiophenyl-3-bromomethyl-quinoline (G13)

A solution of PBr₃ (8.4 g, 31 mmol) in CH₂Cl₂ (40 ml) was added to the mixture of F13 (5.0 g, 15.5 mmol) in CH₂Cl₂ (30 ml) at 0° C. The resulting mixture was stirred for 10 minutes at 0° C. and then for 2 hour at room temperature before quenching with a saturated aqueous NaHCO₃ solution to pH 8. The mixture was added to CH₂Cl₂ and the organic layer was separated, washed with water, dried over Na₂SO₄, and concentrated to obtain the title compound (5.2 g, 86.8%), mp: 98˜100° C. which was used without further purification.

Preparation Example 19 Preparation of compounds G1˜40

Compounds G1˜40 were prepared in the manner similar to the method of Preparation example 18, when Compounds F1˜40 were used as the material respectively. The data of yield, and melting points (Mp.) of compounds G1˜40 were shown in Table 21˜30.

Preparation Example 20 6,7,8-Trifluoro-4-thiophenyl-3(diphenylphosphorylmethyl)-quinoline (B13)

A solution of G13 (5.2 g, 13.4 mmol) and ethyl diphenylphosphinite (6.2 ml, 27 mmol) in toluene (25 ml) was refluxed for 2 h during which time the precipitated solid developed. After cooling to room temperature, the solid was isolated by filtration and washed with toluene. The product was then dried to obtain the title compound (6.6 g, 96.9% yield), mp: 244-245° C.

Preparation Example 21 Preparation of compounds B1˜40

Compounds B1˜40 were prepared in the manner similar to the method of Preparation example 20, when Compounds G1˜40 were used as the material respectively. The data of yield and melting points (Mp.) of compounds G1˜40 were shown in Table 21˜30.

Preparation Example 22 tert-Butyl (3R,5S,6E)-7-[6,7,8-trifluoro-4-thiophenyl-quinoline-3-yl]-3,5-dihydroxy-3,5-O-isopropylidene-6-heptenoate (D13)

1.2 ml (3 mmol) of 2.5 mol/L hexane solution of n-BuLi was added to a solution of 2,2,6,6-tetramethylpiperidine (0.5 g, 3 mmol) in anhydrous THF (10 ml) at 0° C. and stirred for 15 minutes under an atmosphere of nitrogen. B13 (1.0 g, 2.0 mmol) was added to the resulting solution at 0° C. and stirred for 1 hour at room temperature. Compound C (0.61 g, 2.4 mmol) in anhydrous THF (2 ml) was added to the solution and stirred for overnight before quenching with saturated aqueous NaHCO₃ solution (20 ml) at 0° C. The resulting mixture was added to EtOAc and the organic layer was separated, washed with brine, dried over Na₂SO₄ and concentrated. The resulting oil was purified by silica gel chromatography (petroleum ether-EtOAc, 5:1) to provide the title compound (0.6 g, 55.8%) as a solid, mp: 169-171° C.

Preparation Example 23 Preparation of compounds D1˜40

Compounds D1˜40 were prepared in the manner similar to the method of Preparation example 22, when Compounds B1˜40 were used as material respectively. The data of yield, melting points (Mp.) and ¹H-NMR spectra of compounds D1˜40 were shown in Table 31˜50.

Preparation Example 24 (4R,6S)-6-[(E)-2-(4-thiophenylquinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (A1)

A solution of D1 (0.44 g, 0.86 mmol) and CF₃COOH (2 ml, 25.8 mmol) in CH₂Cl₂ (10 ml) was stirred at 0° C. for 8 h before quenching with a saturated aqueous NaHCO₃ solution. The mixture was added to EtOAc and the organic layer was separated, washed with water, dried over Na₂SO₄, and concentrated. The resulting oil was purified by silica gel chromatography (petroleum ether-EtOAc, 2:1) to provide the title compound (0.30 g, 91.7%) as white solid. mp: 102-104° C.

Preparation Example 25 (4R,6S)-6-[(E)-2-(6,7,8-trifluoro-4-thiophenylquinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (A13)

A solution of D13 (0.47 g, 0.86 mmol) and CF₃COOH (2 ml, 25.8 mmol) in CH₂Cl₂ (10 ml) was stirred at 80° C. for 1 h before quenching with a saturated aqueous NaHCO₃ solution. The mixture was added to EtOAc and the organic layer was separated, washed with water, dried over Na₂SO₄, and concentrated. The resulting oil was purified by silica gel chromatography (petroleum ether-EtOAc, 2:1) to provide the title compound (0.30 g, 81.4%) as white solid. mp: 177-178° C.

Preparation Example 26 (4R,6S)-6-[(E)-2-(4-(4-fluoro-thiophenylquinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (A2)

A solution of D2 (0.86 mmol) and concentrated HCl (4 ml) in t-BuOMe (10 ml) was stirred at 25° C. for 8 h before quenching with a saturated aqueous NaHCO₃ solution. The mixture was added to EtOAc and the organic layer was separated, washed with water, dried over Na₂SO₄, and concentrated. The resulting oil was purified by silica gel chromatography (petroleum ether-EtOAc, 2:1) to provide the title compound.

Preparation Example 27 (4R,6S)-6-[(E)-2-(4-(3-methoxy-thiophenylquinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (A3)

A solution of D3 (0.86 mmol) and CH₃COOH (0.5 ml) in CHCl₃ (10 ml) was stirred at 30° C. for 4 h before quenching with a saturated aqueous NaHCO₃ solution.

The mixture was added to EtOAc and the organic layer was separated, washed with water, dried over Na₂SO₄, and concentrated. The resulting oil was purified by silica gel chromatography (petroleum ether-EtOAc, 2:1) to provide the title compound.

Preparation Example 28 (4R,6S)-6-[(E)-2-(4-(4-isopropyl-thiophenylquinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (A4)

A solution of D4 (0.86 mmol) and CH₃COOH (0.5 ml) in toluene (10 ml) was stirred at 30° C. for 3 h before quenching with a saturated aqueous NaHCO₃ solution. The mixture was added to EtOAc and the organic layer was separated, washed with water, dried over Na₂SO₄, and concentrated. The resulting oil was purified by silica gel chromatography (petroleum ether-EtOAc, 2:1) to provide the title compound.

Preparation Example 29 Preparation of Compound of A-A40

Compounds A1˜40 were prepared in the manner similar to the method of Preparation example 24, when Compounds D1˜40 were used as material respectively. The data of yield, melting points (Mp.) and ¹H-NMR spectra of compounds A1˜40 were shown in Table 51˜70.

Efficacy Example HMG CoA Reductase Inhibition Assay of Some Quinoline Compounds A In Vitro

The HMG CoA reductase inhibitory activity of compounds A in vitro was assayed following the method of “Kim H J et al: Characterization of β-hydroxy-β-methylglutaryl coenzyme A reductase inhibitor from Pueraria thunbergiana, J Agric Food Chem 2005, 53:5882-5888”.

The HMG CoA reductase was extracted from the liver of Male Holtzman-Sprague-Dawley rats.

The positive control experiment was made with rosuvastatin, pitavastatin, atorvastatin, and fluvastatin. The negative control experiment was made without any inhibitor. The blank control experiment was made without HMG CoA and inhibitor.

3-Hydroxy-3-methylglutaryl-CoA (HMG CoA) reductase catalyzes the reduction of 1 mol HMG CoA and 2 mol NADPH to afford mevalonic acid and NADP.

NADPH shows a maximum absorption at 340 nm, and NADP shows no absorption at 340 nm. The reduction rate determined in this study was measured by the descending rate of ultraviolet absorption value at 340 nm. After addition of the inhibitor, the inhibitory activity of inhibitor on the enzyme can be calculated by the difference of ultraviolet absorption value. The in vitro HMG CoA reductase inhibition of some quinoline compounds in the invention was assayed by the method describe above.

The concentration of an inhibitor required to inhibit 50% of the HMG CoA reductase under the above assay conditions was defined as IC₅₀. The UV absorbance was measured in eight levels for each sample. A statistical analysis was performed by standard curve using mean values of triplicate measurements (n=3). The results were seen in Table 71.

The data of Table 71 showed that some quinoline compounds in this invention were more potent than fluvastatin, rosuvastatin or pitavastatin in HMG CoA reductase inhibition.

TABLE 1 Ethyl 4-substituted thiophenyl-quinoline-3-carboxylate (E1~4)

¹H-NMR δ ppm in CDCl₃ No R Formula Purifi- cation yield % Mp ° C. 2H 8H 5H 6H 7H

Et E1 H C₁₈H₁₅NO₂S A 88.9 Oil 9.07 8.43 8.14 7.76-7.72 7.55-7.51 7.20-7.14 (m, 5H) 4.25 (q, 2H, J = 7.2) s dd, d, m m 1.28 (t, 3H, J = 7.2) J = 8.4, J = 8.4 1.2 E2 p-F C₁₈H₁₄FNO₂S B 89.9 52-4 9.05 8.43 8.14 7.79-7.75 7.59-7.55 7.21 (dd, 2H, 4.30 (q, 2H, J = 7.6) s dd, d, m m J = 11.8, 5.0) 1.33 (t, 3H, J = 7.2) J = 8.6, J = 8.4 6.93 (t, 2H, J = 6.4) 0.8 E3 m-OCH₃ C₁₉H₁₇NO₃S A 90.2 Oil 9.06 8.43 8.13 7.77-7.73 7.57-7.52 7.10 (t, 1H, J = 8.0) 4.29 (q, 2H, J = 7.2) s dd, dd, m m 6.75-6.67 (m, 3H) 1.31 (t, 3H, J = 7.2) J = 8.4, J = 8.8, 3.66 (s, 3H) 1.2 1.2 E4 p-CH(CH₃)₂ C₂₁H₂₁NO₂S B 98.0 44-6 9.03 8.19 8.13 7.76-7.72 7.56-7.52 7.16-7.06 (m, 4H) 4.21 (q, 2H, J = 6.8) s dd, d, m m 2.82 (t, 1H, J = 7.2) 1.27 (t, 3H, J = 6.8) J = 8.4, J = 8.4 1.18 (d, 6H, J = 6.8) 0.8 A: purified by silica gel chromatography (petroleum ether-EtOAc) B: recrystalized by toluene/petroleum ether

TABLE 2 Ethyl 7-chloro-4-substituted thiophenyl-quinoline-3-carboxylate (E5~8)

¹H-NMR δ ppm in CDCl₃ R Formula Purifi- cation yield % Mp ° C. 2H 5H 8H 6H

Et E5 H C₁₈H₁₃ClNO₂S B 79.6 82-4 9.06 8.37 8.14, 7.48 7.22-7.16 (m, 5H) 4.26 (q, 2H, J = 7.2) s d, d, dd, 1.30 (t, 3H, J = 6.8) J = 9.2 J = 2.0 J = 9.2, 2.0 E6 p-F C₁₈H₁₃ClFNO₂S B 97.1 91-4 9.04 8.36 8.13 7.50 7.21-7.18 (m, 2H) 4.29 (q, 2H, J = 7.2) s d, d, dd, 6.95-6.91 (m, 2H) 1.32 (t, 3H, J = 7.2) J = 9.2 J = 2.0 J = 9.2, 2.0 E7 m-OCH₃ C₁₉H₁₆ClNO₃S A 95.8 76-8 9.06 8.35 8.12 7.47 7.11-7.09 (m, 1H) 4.29 (q, 2H, J = 6.8) s d, d, dd, 6.74-6.70 (m, 3H) 1.31 (t, 3H, J = 6.8) J = 9.2 J = 2.0 J = 9.2, 2.0 3.68 (s, 3H) E8 p-CH(CH₃)₂ C₂₁H₂₀ClNO₂S B 85.8 108-10 9.01 8.40 8.11 7.47 7.14-7.07 (m, 4H) 4.22 (q, 2H, J = 7.6) s d, d, dd, 2.85-2.81 (m, 1H) 1.28 (t, 3H, J = 7.2) J = 9.2 J = 2.0 J = 9.2, 2.0 1.18 (d, 6H, J = 6.8) A: purified by silica gel chromatography (petroleum ether-EtOAc) B: recrystallized by toluene/petroleum ether

TABLE 3 Ethyl 6-fluoro-7-chloro-4-substituted thiophenyl-quinoline-3-carboxylate (E9~12)

¹H-NMR δ ppm in CDCl₃ No R Formula Purifi- cation yield % Mp ° C. 2H 8H 5H

Et E9 H C₁₈H₁₃ClFNO₂S Petroleum 91.7  94-6 9.02 8.22, 8.14, 7.26-7.17 (m, 5H) 4.28 (q, 2H, J = 7.2) ether s d, d, 1.33 (t, 3H, J = 7.6) J = 7.6 J = 10.4 E10 p-F C₁₈H₁₂ClF₂NO₂S Petroleum 88.5 100-2 9.00 8.22 8.13 7.21 (dd, 2H, J = 11.8, 5.0) 4.31 (q, 2H, J = 7.2) ether s d, d, 6.95 (t, 2H, J = 7.6) 1.33 (t, 3H, J = 7.6) J = 6.8 J = 10.4 E11 m-OCH₃ C₁₉H₁₅ClFNO₃S A 98.0  50-2 9.01 8.20 8.12 7.15-7.11 (m, 1H) 4.29 (q, 2H, J = 7.2) s d, d, 6.74-6.71 (m, 3H) 1.28 (t, 3H, J = 7.6) J = 7.2 J = 10.4 3.69 (s, 3H) E12 p-CH(CH₃)₂ C₂₁H₁₉ClFNO₂S B 89.2 116-8 8.98 8.20 8.17 7.15-7.09 (m, 4H) 4.24 (q, 2H, J = 7.6) s d, d, 2.84 (m, 2H) 1.29 (t, 3H, J = 7.2) J = 7.2 J = 10.4 1.20 (s, 3H), 1.19 (s, 3H) A: purified by silica gel chromatography (petroleum ether-EtOAc) B: recrystallized by toluene/petroleum ether

TABLE 4 Ethyl 6,7,8-trifluoro-4-substituted thiophenyl-quinoline-3-carboxylate (E13~16)

¹H-NMR δ ppm in CDCl₃ No R Formula yield* % Mp ° C. 2H 5H

Et E13 H C₁₈H₁₂F₃NO₂S 59.6 92-4 9.04 8.05-7.99 7.26-7.17 (m, 5H) 4.27 (q, 2H, J = 7.2) s m 1.29 (t, 3H, J = 6.4) E14 p-F C₁₈H₁₁F₄NO₂S 60.0 126-8  9.04 8.05-8.00 7.24-7.20 (m, 2H) 4.30 (q, 2H, J = 7.2) s m 6.99-6.94 (m, 2H) 1.32 (t, 3H, J = 7.2) E15 m-OCH₃ C₁₉H₁₄F₃NO₃S 55.8 70-2 9.07 8.06-8.01 7.16 (t, 1H, J = 8.0) 4.31 (q, 2H, J = 7.2) s m 6.77-6.72 (m, 3H) 1.32 (t, 3H, J = 6.8) 3.72 (s, 3H) E16 p-CH(CH₃)₂ C₂₁H₁₈F₃NO₂S 52.4 86-8 9.01 8.08-8.03 7.15-7.10 (m, 4H) 4.23 (q, 2H, J = 7.2) s m 2.86-2.83 (m, 1H) 1.28 (t, 3H, J = 7.2) 1.19 (d, 6H, J = 6.8) *purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 5 Ethyl 4,7-disubstituted thiophenyl-quinoline-3-carboxylate (E17~20)

¹H-NMR δ ppm in CDCl₃ No R Formula yield* % Mp ° C. 2H 5H 8H 6H

Et E17 H C₂₄H₁₉NO₂S₂ 80.0  98-100 8.98 8.29 7.76 7.34 7.56-7.54 (m, 2H), 7.42-7.40 (m, 3H), 4.24 (q, 2H, s d, d, dd, 7.22-7.15 (m, 5H) J = 7.2) J = 9.2 J = 1.6 J = 8.8, 1.28 (t, 3H, 1.6 J = 7.6) E18 p-F C₂₄H₁₇F₂NO₂S₂ 91.2 68-70 8.96 8.28 7.66 7.56 7.56 (dd, 2H, J = 10.0, 5.2), 7.20-7.10 4.27 (q, 2H, s d, s dd, (m, 4H), 6.91 (t, 2H, J = 7.4) J = 7.2) J = 9.2 J = 8.8, 1.30 (t, 3H, 5.6 J = 7.2) E19 m-OCH₃ C₂₆H₂₃NO₄S₂ 88.1 Oil 8.99 8.29 7.80 7.36 7.31 (t, 1H, J = 8.0), 7.14-7.07 (m, 3H), 4.27 (q, 2H, s d, d, dd, 6.95-6.92 (m, 1H), 6.73-6.68 (m, 3H), J = 7.2) J = 9.2 J = 2.0 J = 8.8, 3.78 (s, 3H), 3.68 (s, 3H) 1.30 (t, 3H, 2.0 J = 7.2) E20 p-CH(CH₃)₂ C₃₀H₃₁NO₂S₂ 93.0 Oil 8.93 8.32 7.71 7.34 7.49 (d, 2H, J = 8.0), 7.28 (d, 2H, J = 8.4), s d, s dd, 7.12-7.06 (m, 4H), 4.11 (q, 2H, J = 8.8 J = 9.2, J = 6.8), 2.95 (m, 1H), 2.83 (m, 1H), 1.6 1.31-1.14 (m, 15H) *purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 6 Ethyl 6-fluoro-4,7-disubstituted thiophenyl-quinoline-3-carboxylate (E21~24)

¹H-NMR δ ppm in CDCl₃ No R Formula Purification yield % Mp ° C. 2H 5H 8H

Et E21 H C₂₄H₁₈FO₂S₂ A 65.3 Oil 8.90 8.02 7.53 7.60-7.57 (m, 2H), 7.46-7.44 4.25 (q, 2H, s d, d, (m, 3H), J = 6.8) J = 11.2 J = 8.0 7.25-7.15 (m, 5H) 1.27 (t, 3H, J = 7.2) E22 p-F C₂₄H₁₆F₃NO₂S₂ Toluene/ 89.0 146-8 8.89 8.02 7.45 7.59 (dd, 2H, J = 7.0, 5.2), 4.28 (q, 2H, hexane s d, d, 7.22-7.15 (m, 4H), J = 7.2) J = 10.8 J = 7.2 6.94 (t, 2H, J = 7.6) 1.31 (t, 3H, J = 6.8) 7.36 (t, 1H, J = 8.0), 7.17-7.01 4.27 (q, 2H, E23 m-OCH₃ C₂₆H₂₂FNO₄S₂ A 60.0 Oil 8.92 8.02 7.56 (m, 3H), J = 7.2) s d, d, 7.00-6.97 (m, 1H), 6.74-6.70 1.27 (t, 3H, J = 11.2 J = 7.6 (m, 3H) J = 6.8) 3.80 (s, 3H), 3.69 (s, 3H) E24 p-CH(CH₃)₂ C₃₀H₃₀FNO₂S₂ Toluene/ 77.7 88-90 8.86 8.05 7.53-7.50 (m, 3H), 7.32 (d, 2H, J = 8.0), 4.22 (q, 2H, hexane s d, 7.13-7.08 (m, 4H), 2.97 (t, 1H, J = 6.8), J = 7.2) J = 11.2 2.84 (t, 1H, J = 6.8), 1.30 (d, 6H, 1.26 (t, 3H, J = 7.2), 1.20 (d, 6H, J = 6.8) J = 7.2) A: purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 7 Ethyl 6,8-difluoro-4,7-disubstituted thiophenyl-quinoline-3-carboxylate (E25~28)

¹H-NMR δ ppm in CDCl₃ No R Formula Purification Yield % Mp ° C. 2H 5H

Et E25 H C₂₄H₁₇F₂O₂S₂ A 65.3 82-4 9.01 7.93 7.39-7.37 (m, 2H), 4.25 (q, 2H, s dd, 7.28-7.19 (m, 8H) J = 7.2) J = 10.2, 1.29 (t, 3H, 2.0 J = 6.8) E26 p-F C₂₄H₁₅F₄NO₂S₂ B 52.6 114-6  8.99 7.91 7.46 (dd, 2H, J = 8.6, 5.2), 4.28 (q, 2H, s dd, 7.23 (dd, 2H, J = 8.6, 4.8), J = 7.2) J = 9.0, 7.00-6.94 (m, 4H) 1.31 (t, 3H, 2.0 J = 6.8) E27 m-OCH₃ C₂₆H₂₁F₂NO₄S₂ A 60.0 Oil 9.02 7.93 7.18-7.13 (m, 2H), 4.28 (q, 2H, s dd, 6.94-6.91 (m, 2H), J = 7.6) J = 10.2, 6.78-6.73 (m, 4H), 3.73 (s, 3H), 1.31 (t, 3H, 1.2 3.71 (s, 3H) J = 7.2) E28 p-CH(CH₃)₂ C₃₀H₂₉F₂NO₂S₂ C 50.0 75-7 8.97 7.94 7.35 (d, 2H, J = 8.0), s dd, 7.16-7.09 (m, 6H), 4.21 (q, 2H, J = 10.4, J = 7.6), 2.0 2.88-2.83 (m, 2H), 1.29-1.19 (m, 15H) A: purified by silica gel chromatography (petroleum ether-EtOAc) B: recrystallized by petroleum ether-EtOAc. C: recrystallized by petroleum ether

TABLE 8 Ethyl 4,6,7-trisubstituted thiophenyl-quinoline-3-carboxylate (E29~32)

¹H-NMR δ ppm in CDCl₃ No R Formula Yield % Mp ° C. 2H 8H 5H

Et E29 H C₃₀H₂₃NO₂S₃ 90.2 110-3  9.10 7.92 7.88 7.59-7.53 (m, 5H), 7.43-7.40 (m, 5H), 4.29 (q, 2H, s s s 7.18 (d, 3H, J = 7.6), 6.88 (d, 3H, J = 7.6) J = 6.8) 1.27 (t, 3H, J = 7.2) E30 p-F C₃₀H₂₀F₃NO₂S₃ 88.0 118-22 8.87 7.97 7.44 7.55 (dd, 2H, J = 7.0, 5.2), 7.34 (dd, 2H, 4.30 (q, 2H, s s s J = 6.8, 5.2), J = 6.8) 7.15 (t, 2H, J = 6.8), 7.04 (t, 2H, J = 8.4), 1.31 (t, 3H, 6.94 (dd, 2H, J = 7.0, 4.4), 6.85 (t, 2H, J = 7 .2) J = 8.4) E31 m-OCH₃ C₃₃H₂₉NO₅S₃ 62.0 Oil 8.89 8.18 7.57 7.34 (t, 1H, J = 8.0), 7.24-7.20 (m, 1H), 4.30 (q, 2H, s s s 7.15-7.12 (m, 1H), 7.09 (t, 1H, J = 2.0) J = 6.8) 7.00-6.97 (m, 1H), 6.74-6.70 (m, 3H) 1.31 (t, 3H, 3.80 (s, 3H), 3.69 (s, 3H) J = 7.2) E32 p-CH(CH₃)₂ C₃₉H₁₄NO₂S₃ 83.5 Oil 8.74 7.98 7.58 7.51 (d, 2H, J = 8.0), 7.30 (d, 4H, J = 8.4), 4.27 (q, 2H, s s s 7.19 (d, 2H, J = 8.4), 7.01 (d, 2H, J = 8.4), J = 7.2) 7.76 (d, 2H, J = 8.0) 1.27 (t, 3H, J = 6.8)

TABLE 9 Ethyl 6-fluoro-4,7,8-trisubstituted thiophenyl-quinoline-3-carboxylate (E33~36)

¹H-NMR δ ppm in CDCl₃ No R Formula Purification Yield % Mp ° C. 2H 5H

Et E33 H C₃₀H₂₂FNO₂S₃ Toluene/ 69.1 128-30 9.05 8.14 7.26-7.11 (m, 15H) 4.23 (q, 2H, hexane s d, J = 6.8) J = 10.8 1.26 (t, 3H, J = 7 .2) E34 p-F C₃₀H₁₉F₄NO₂S₃ EtOH 89.3 80-3 9.03 8.11 7.28-7.21 (m, 6H), 4.26 (q, 2H, s d, 6.97-6.87 (m, 6H) J = 6.8) J = 10.4 1.26 (t, 3H, J = 7.2) E35 m-OCH₃ C₃₃H₂₈FNO₅S₃ A 60.3 104-6  9.07 8.14 7.17 (m, 3H), 4.27 (q, 2H, s d, 6.82-6.64 (m, 9H), J = 6.8) J = 10.4 3.72 (s, 3H), 3.70 (s, 1.29 (t, 3H, 3H), 3.69 (s, 3H) J = 6.8) E36 p-CH(CH₃)₂ C₃₉H₄₀FNO₂S₃ A 65.8 Oil 9.04 8.14 7.18-7.02 (m, 12H), 4.20 (q, 2H, J = 6.8), s d, 2.88-2.81 (m, 3H), J = 11.2 1.33-1.15 (m, 2H) A: purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 10 Ethyl 4,6,7,8-tetrasubstituted thiophenyl-quinoline-3-carboxylate (E37~40)

¹H-NMR δ ppm in CDCl₃ No R Formula Recrystalized solvent Yield % Mp ° C. 2H 5H

Et E37 H C₃₆H₂₇NO₂S₄ petroleum ether 98.0  91-3 8.90 7.88 7.52-7.40 (m, 5H), 7.30-7.04 (m, 13H), 4.25 (q, 2H, s s 6.85-6.83 (m, 2H) J = 6.8) 1.27 (t, 3H, J = 6.8) E38 p-F C₃₆H₂₃F₄NO₂S₄ toluene/hexane 90.2 126-8 8.87 7.72 7.40 (dd, 2H, J = 9.8, 5.2), 7.19 (dd, 4.27 (q, 2H, s s 2H, J = 8.4, 5.2), J = 7.6) 7.14-7.10 (m, 4H), 6.93-6.80 (m, 8H) 1.27 (t, 3H, J = 7.2) E39 m-OCH₃ C₄₀H₃₅NO₆S₄ A 76.9 oil 8.92 7.95 7.29 (t, 1H, J = 8.0), 7.09 (t, 1H, 4.26 (q, 2H, s s J = 7.6), 7.05-6.94 (m, J = 6.8) 5H), 6.73-6.58 (m, 1.27 (t, 3H, 7H), 6.44-6.37 (m, 2H), 3.76 (m, J = 7.2) 3H), 3.67 (s, 3H), 3.65 (s, 3H), 3.64 (s, 3H) E40 p-CH(CH₃)₂ C₄₈H₅₁NO₂S₄ A 84.3 oil 8.86 7.82 7.34-7.25 (m, 4H), 7.13-7.10 (m, 4.20 (q, 2H, s s 2H), 7.06-6.95 (m, 8H), J = 6.8) 6.77-6.75 (m, 2H), 3.00-2.97 (m, 0.86 (t, 3H, 1H), 2.85-2.76 (m, 3H), J = 5.2) 1.34-1.16 (m, 24H) A: purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 11 4-substituted thiophenyl quinoline-3-methanol (F1~4)

¹H-NMR δ ppm in CDCl₃ No R Formula Recrystalized solvent Yield % Mp ° C. 2H 8H 5H 6H 7H

CH₂ F1 H C₁₆H₁₃NOS petroleum 64.6 144-6 9.09 8.43 8.14 7.73-7.67 7.56-7.52 7.04-6.89 (m, 5.03 ether/EtOAc s d, d, m m 5H) s J = 8.4 J = 8.4 F2 p-F C₁₆H₁₂FNOS Et₂O 76.5 130-2 9.10 8.43 8.12 7.72-7.67 7.56-7.52 7.05-7.01 (m, 5.04 s m dd, m m 2H) s J = 8.6, 6.90-6.85 (m, 0.8 2H) F3 m-OCH₃ C₁₇H₁₅NO₂S A 61.5 122-4 9.10 8.38 8.11 7.70-7.66 7.54-7.50 7.04 (t, 1H, 5.02 s d, d, m m J = 8.0) s J = 8.4 J = 8.0 6.65-6.54 (m, 3H) 3.63 (s, 3H) F4 p-CH(CH₃)₂ C₁₉H₁₉NOS petroleum 63.9 100-2 9.09 8.45 8.14 7.72-7.68 7.56-7.52 7.05-6.96 (m, 4H) 5.02 ether/EtOAc s d, d, m m 2.82-2.78 (m, s J = 8.4 J = 8.0 1H), 1.17 (d, 6H, J = 7.2) A: purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 12 7-chloro-4-substituted thiophenyl-quinoline-3-methanol (F5~8)

¹H-NMR δ ppm in CDCl₃ No R Formula Yield* % Mp ° C. 2H 5H 8H 6H

CH₂ F5 H C₁₆H₁₁ClNOS 52.8 122 9.11 8.34 8.13 7.48 7.21-7.14 (m, 3H), 5.01 s d, d, dd, 7.03-7.09 (m, 2H) s J = 9.2 J = 2.0 J = 8.8, 2.0 F6 p-F C₁₆H₁₁ClFNOS 63.6 142-6  9.09 8.31 8.11 7.48 7.05-7.02 (m, 2H), 5.02 s d, d, dd, 6.92-6.88 (m, 2H) s J = 9.2 J = 2.0 J = 8.8, 2.0 F7 m-OCH₃ C₁₇H₁₄ClNO₂S 69.8 118 9.10 8.33 8.12 7.48 7.09 (t, 1H, J = 8.0), 5.02 s d, d, dd, 6.69-6.66 (m, 1H), s J = 8.8 J = 2.0 J = 8.8, 6.59-6.54 (m, 2H), 2.0 3.67 (s, 3H) F8 p-CH(CH₃)₂ C₁₉H₁₈ClNOS 53.3 88-90 9.09 8.38 8.12 7.47 7.06-6.96 (m, 4H), 5.00 s d, d, dd, 2.82-2.79 (m, 1H), s J = 9.2 J = 2.0 J = 8.8, 1.17 (d, 6H, J = 7.2) 2.0 A: purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 13 6-fluoro-7-chloro-4-substituted thiophenyl--quinoline-3-methanol (F9~12)

¹H-NMR δ ppm in CDCl₃ No R Formula Recrystalized solvent Yield % Mp ° C. 2H 8H 5H

CH₂ F9 H C₁₆H₁₁ClFNOS Toluene 61.8 120-4 9.12 s 8.25 d, 8.12 d, 7.25-7.18(m, 3H), 5.02 s J = 6.8 J = 10.0 7.06-7.03(m, 2H) F10 p-F C₁₆H₁₀ClF₂NOS Toluene 62.2 154-6 9.09 s 8.23 d, 8.11 d, 7.07-7.04(m, 2H), 5.03 s J = 7.6 J = 10.4 6.95-6.91(m, 2H) F11 m-OCH₃ C₁₇H₁₃ClFNO₂S Toluene 75.6 117-8 9.11 s 8.24 d, 8.14 d, 7.15-7.11(m, 1H), 5.04 s J = 7.6 J = 10.4 6.73-6.70(m, 1H), 6.60-6.57(m, 2H), 3.71(s, 3H) F12 p-CH(CH₃)₂ C₁₉H₁₇ClFNOS A 73.9 132-4 9.06 s 8.19 d, 8.13 d, 7.06(dd, 2H, J = 6.4, 2.0), 5.00 s J = 6.8 J = 10.8 6.96 dd, 2H, J = 6.8, 2.0) 2.81(m, 2H), 1.17(d, 6H, J = 6.8) A: purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 14 6,7,8-trifluoro-4-substituted thiophenyl-quinoline-3-methanol(F13~16)

¹H-NMR δ ppm in CDCl₃ No R Formula Yield* % Mp ° C. 2H 5H

CH₂ F13 H C₁₆H₁₀F₃NOS 70.6 126-8 9.15 s 8.02-7.97 m 7.24-7.17(m, 3H), 7.03-7.01(m, 2H) 5.03 s F14 p-F C₁₆H₉F₄NOS 63.2 140-2 9.13 s 8.00-7.95 m 7.06-7.02(m, 2H), 6.92(t, 2H, J = 7.2) 5.03 s F15 m-OCH₃ C₁₇H₁₂F₃NO₂S 63.2 100-2 9.16 s 8.03-7.98 m 7.13(t, 1H, J = 8.4), 6.73-6.70(m, 1H) 5.04 s 6.58-6.55(m, 2H), 3.70(s, 3H) F16 p-CH(CH₃)₂ C₁₉H₁₆F₃NOS 76.7  99-102 9.13 s 8.05-8.00 m 7.10-7.06(m, 2H), 6.99-6.96(m, 2H) 5.02 s 2.84-2.81(m, 1H), 1.20-1.17(m, 6H) A: purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 15 4,7-disubstituted thiophenyl-quinoline-3-methanol(F17~20)

¹H-NMR δ ppm in CDCl₃ No R Formula Yield* % Mp ° C. 2H 5H 8H 6H

CH₂ F17 H C₂₂H₁₇NOS₂ 53.1 104 9.00 s 8.27 d, 7.83 d, 7.54-7.52(m, 2H), 7.13-7.08(m, 4H), 4.97 s J = 8.8 J = 1.6 7.19-7.12(m, 3H), 6.91-6.87(m, 2H)  F18 p-F C₂₂H₁₅F₂NOS₂ 66.6 106-8 9.00 s 8.25 d, 7.73 d, 7.34 dd, 7.56-7.52(m, 2H), 4.98 s J = 9.2 J = 1.6 J = 9.2, 2.4 7.13-7.08(m, 2H), 7.05-7.01(m, 2H), 6.91-6.87(m, 2H) F19 m-OCH₃ C₂₄H₂₃₂₁NO₃S₂ 49.4  82-4 9.02 s 8.28 d, 7.88 d, 7.39 dd, 7.29(t, 1H, 4.98 s J = 8.8 J = 1.6 J = 8.8, 2.0 J = 8.0),7.12-7.06(m, 3H), 6.92-6.89(m, 1H), 6.68-6.65(m, 1H), 6.60-6.55(m, 2H), 3.78(s, 3H), 3.68(s, 3H) F20 p-CH(CH₃)₂ C₂₈H₂₉NOS₂ 63.5 114 8.97 s 8.30 d, 7.77 s 7.36 dd, 7.48(d, 2H, J = 8.4), 7.26(d, 4.96 s J = 9.2 J = 8.8, 1.6 2H, J = 8.0), 7.04(d, 2H, J = 8.0), 6.95(d, 2H, J = 8.0), 2.95-2.92(m, 1H), 2.83-2.79(m, 1H), 1.28(d, 2H, J = 6.8), 1.17(d, 2H, J = 7.2) A: purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 16 6-fluoro-4,7-disubstituted thiophenyl-quinoline-3-methanol(F21~24)

¹H-NMR δ ppm in CDCl₃ No R Formula Recrystalized solvent Yield % Mp ° C. 2H 5H 8H

CH₂ F21 H C₂₂H₁₆FNOS₂ A 50.6  88-90 8.91 s 7.97 d, 7.60 d, 7.54-7.53(m, 2H), 7.40-7.39(m, 3H), 4.92 s J = 11.2 J = 7.2 7.18-7.11(m, 3H), 6.99(d, 2H, J = 7.2) F22 p-F C₂₂H₁₄F₃NOS₂ toluene 87.5 108-10 8.95 s 7.99 d, 7.52 d, 7.60-7.59(m, 2H), 7.15(t, 2H, J = 8.0) 4.98 s J = 11.2 J = 7.6 7.06-7.03(m, 2H), 6.92(t, 2H, J = 8.0) F23 m-OCH₃ C₂₄H₂₀FNO₃S₂ A 45.9  93-5 8.95 s 8.01 d, 7.67 d, 7.33(t, 1H, J = 8.0), 7.15-7.08(m, 3H), 4.96 s J = 11.2 J = 6.8 6.97-6.94(m, 1H), 6.70-6.67(m, 1H), 6.58-6.56(m, 2H), 3.79(s, 3H), 3.69(s, 3H) F24 p-CH(CH₃)₂ C₂₈H₂₈FNOS₂ EtOH/ 59.8 126-8 8.91 s 8.03 d, 7.55 d, 7.53-7.50(m, 2H), 7.31(d, 2H, J = 8.4), 4.95 s petroleum J = 11.2 J = 8.0 7.06(d, 2H, J = 8.4), 6.97-6.95(m, 2H), ether 2.98-2.94(m, 1H), 2.83-2.78(m, 1H), 1.30-1.27(m, 6H), 1.18(d, 6H, J = 6.8) A: purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 17 6,8-difluoro-4,7-disubstituted thiophenyl-quinoline-3-methanol(F25~28)

¹H-NMR δ ppm in CDCl₃ No R Formula Recrystalized solvent Yield % Mp ° C. 2H 5H

CH₂ F25 H C₂₂H₁₅F₂NOS₂ A 73.7 134-6 9.14 s 7.92 dd, 7.38-7.25(m, 2H), 7.25-7.14(m, 6H), 5.02 s J = 9.6, 2.0 7.04-7.02(m, 2H) F26 p-F C₂₂H₁₃F₄NOS₂ Petroleum ether/ 75.7 149-50 9.12 s 7.88 d, 7.45(dd, 2H, J = 7.6, 5.2), 5.03 s EtOH J = 10.0 7.06(dd, 2H, J = 8.0, 5.2), 6.98-6.90(m, 4H) F27 m-OCH₃ C₂₄H₁₉F₂NO₃S₂ A 57.2 122-4 9.14 s 7.93 dd, 7.18-7.10(m, 2H), 6.93-6.89(m, 2H), 5.03 s J = 10.0, 1.6 6.77-6.74(m, 2H), 6.59-6.57(m, 2H), 3.73(s, 3H), 3.70(s, 3H) F28 p-CH(CH₃)₂ C₂₈H₂₇F₂NOS₂ EtOAc 71.8 152-4 9.10 s 7.95 dd, 7.35(d, 2H, J = 7.4), 7.13-7.07(m, 4H), 5.01 s J = 10.4, 2.5 7.00-6.97(m, 2H), 2.87-2.81(m, 2H), 1.21-1.18(m, 12H) A: purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 18 4,6,7-trisubstituted thiophenyl-quinoline-3-methanol(F29~32)

¹H-NMR δ ppm in CDCl₃ No R Formula Recrystalized solvent Yield % Mp ° C. 2H 8H 5H

CH₂ F29 H C₂₈H₂₁NOS₃ Petroleum 60.9 190-3 9.13 s 7.93 s 7.88 s 7.60-7.54(m, 5H), 7.44-7.40(m, 5H), 4.88 s ether 7.19-7.17(m, 3H), 6.88-6.87(m, 2H) F30 p-F C₂₈H₁₈F₃NOS₃ Petroleum 74.1 174-6 8.91 s 7.87 s 7.52 s 7.57-7.52(m, 2H), 7.34-7.30(m, 2H), 4.98 s ether 7.14(t, 2H, J = 8.0), 7.01(t, 2H, J = 8.4), 6.88-6.87(m, 4H) F31 m-OCH₃ C₃₁H₂₇NO₄S₃ A 68.7 112-5 8.90 s 8.12 s 7.64 s 7.32(t, 1H, J = 8.0), 7.19-6.82(m, 4.94 s 8H), 6.64-6.62(m, 1H), 6.43(t, 1H, J = 2.0), 6.39-6.36(m, 1H), 3.78(s, 3H), 3.71(s, 3H), 3.66(s, 3H) F32 p-CH(CH₃)₂ C₃₇H₃₉NOS₃ A 71.8  96-8 8.84 s 7.99 s 7.57 s 7.50(d, 2H, J = 8.0), 7.29(d, 2H, 4.93 s J = 8.4), 7.18(d, 2H, J = 8.4), 6.99(d, 2H, J = 8.4), 6.74(d, 2H, J = 8.0), 2.97-2.92(m, 2H), 2.84-2.81(m, 2H), 1.30-1.20(m, 18H) A: purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 19 6-fluoro-4,7,8-trisubstituted thiophenyl-quinoline-3-methanol(F33~36)

¹H-NMR δ ppm in CDCl₃ No R Formula Recrystalized solvent Yield % Mp ° C. 2H 5H

CH₂ F33 H C₂₈H₂₀FNOS₃ A 65.0 154-6 9.17 s 8.15 d, 7.26-7.04(m, 15H) 5.00 s J = 10.8 F34 p-F C₂₈H₁₇F₄NOS₃ Petroleum 78.5 200-3 9.15 s 8.10 d, 7.26-7.21(m, 5H), 7.08-7.04(m, 2H), 5.00 s ether J = 10.8 6.95-6.86(m, 5H) F35 m-OCH₃ C₃₁H₂₆FNO₄S₃ A 66.9 110-2 9.17 s 8.15 d, 7.14-7.04(m, 3H), 6.80-6.78(d, 1H, 5.00 s J = 10.4 J = 8.0), 6.75-6.67(m, 5H), 6.64-6.61(m, 1H), 6.59-6.57(m, 2H), 3.73-3.68(m, 9H) F36 p-CH(CH₃)₂ C₃₇H₃₈FNOS₃ A 41.3 140-2 9.20 s 8. 19 d, 7.21-7.02(m, 12H), 2.91-2.82(m, 3H), 5.03 s J = 10.8 1.25-1.18(m, 18H) A: purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 20 4,6,7,8-tetrasubstituted thiophenyl-quinoline-3-methanol(F37~40)

¹H-NMR δ ppm in CDCl₃ No R Formula Recrystalized solvent Yield % Mp ° C. 2H 5H

CH₂ F37 H C₃₄H₂₅NOS₄ A 46.8 163-5 8.98 s 7.81 s 7.39-7.28(m, 5H), 7.20-7.03(m, 13H), 4.94 s 6.72-6.69(m, 2H) F38 p-F C₃₄H₂₁F₄NOS₄ EtOH 87.2 190-2 9.00 s 7.61 s 7.37-7.34(m, 2H), 7.20-7.16(m, 2H), 4.96 s 7.13-7.09(m, 2H), 7.07-7.02(m, 2H), 6.93-6.79(m, 6H), 6.69-6.65(m, 2H) F39 m-OCH₃ C₃₈H₃₃NO₅S₄ A 55.4 116-8 9.01 s 7.87 s 7.22(t, 1H, J = 8.0), 7.09(t, 1H, J = 8.4), 4.94 s 7.04-6.92(m, 5H), 6.73-6.55(m, 7H), 6.30-6.24(m, 2H), 3.70(s, 3H), 3.67(s, 3H), 3.66(s, 3H), 3.64(s, 3H) F40 p-CH(CH₃)₂ C₄₆H₄₉NOS₄ A 55.0 170-3 8.96 s 7.78 s 7.30(d, 2H, J = 7.0), 7.19(d, 2H, J = 8.0), 4.93 s 7.12(d, 2H, J = 7.4), 7.06-6.94(m, 8H), 6.65(d, 2H, J = 7.4), 2.96-2.93(m, 1H), 2.86-2.76(m, 3H), 1.29-1.14(m, 24H) A: purified by silica gel chromatography (petroleum ether-EtOAc).

TABLE 21 4-substituted thiophenyl-3-bromomethyl(or 3-diphenyl- phosphoryl-methyl)-quinoline (G1~4 or B1~4)

No R X Formula Yield % Mp ° C. G1 H Br C₁₆H₁₂BrNS  67.2 156-60 G2 p-F Br C₁₆H₁₁BrFNS  76.5 130-2 G3 m-OCH₃ Br C₁₇H₁₄BrNOS  85.4 100 G4 p-CH(CH₃)₂ Br C₁₉H₁₈BrNS — — B1 H P(O)Ph₂ C₂₈H₂₃NOPS  81.5 228-30 B2 p-F P(O)Ph₂ C₂₈H₂₂FNOPS 100 184-5 B3 m-OCH₃ P(O)Ph₂ C₂₉H₂₅NO₂PS 100 197-8 B4 p-CH(CH₃)₂ P(O)Ph₂ C₃₁H₂₉NOPS  79.4* 190-2 *: two steps' yield

TABLE 22 7-chloro-4-substituted thiophenyl-3-bromomethyl(or 3-diphenyl- phosphoryl-methyl)-quinoline (G5~8 or B5~8)

No R X Formula Yield % Mp ° C. G5 H Br C₁₆H₁₁BrClNS  87.0 104-6 G6 p-F Br C₁₆H₁₀BrClFNS  83.3 112-4 G7 m-OCH₃ Br C₁₇H₁₃BrClNOS  86.1  92-4 G8 p-CH(CH₃)₂ Br C₁₉H₁₇BrClNS  86.5 101-2 B5 H P(O)Ph₂ C₂₈H₂₁ClNOPS  98.7 210-2 B6 p-F P(O)Ph₂ C₂₈H₂₀ClFNOPS 100 192-4 B7 m-OCH₃ P(O)Ph₂ C₂₉H₂₃ClNO₂PS  92.9 194-6 B8 p-CH(CH₃)₂ P(O)Ph₂ C₃₁H₂₇ClNOPS  99.8 238-40 *: two steps' yield

TABLE 23 7-chloro-6-fluoro-4-substituted thiophenyl-3-bromomethyl(or 3-diphenyl-phosphoryl-methyl)-quinoline (G9~12 or B9~12)

No R X Formula Yield % Mp ° C. G9 H Br C₁₆H₁₀BrClFNS  85 130-2 G10 p-F Br C₁₆H₉BrClF₂NS  84.5 156-7 G11 m-OCH₃ Br C₁₇H₁₂BrClFNOS  83 108-10 G12 p-CH(CH₃)₂ Br C₁₉H₁₆BrClFNS  85.0 132-4 B9 H P(O)Ph₂ C₂₈H₂₀ClFNOPS  88.9 238-40 B10 p-F P(O)Ph₂ C₂₈H₁₉ClF₂NOPS 100 250-2 B11 m-OCH₃ P(O)Ph₂ C₂₉H₂₂ClFNO₂PS  87.8 216-8 B12 p-CH(CH₃)₂ P(O)Ph₂ C₃₁H₂₆ClFNOPS 100 234-6

TABLE 24 6,7,8-trifluoro-4-substituted thiophenyl-3-bromomethyl(or 3-diphenyl-phosphoryl-methyl)-quinoline (G13~16 or B13~16)

No R X Formula Yield % Mp ° C. G13 H Br C₁₆H₉BrF₃NS 86.8  98-100 G14 p-F Br C₁₆H₈BrF₄NS — — G15 m-OCH₃ Br C₁₇H₁₁BrF₃NOS 80.3 112-4 G16 p-CH(CH₃)₂ Br C₁₉H₁₅BrF₃NS 86.6  86-8 B13 H P(O)Ph₂ C₂₈H₁₉F₃NOPS 96.9 244-5 B14 p-F P(O)Ph₂ C₂₈H₁₈F₄NOPS 84.2* 212-3 B15 m-OCH₃ P(O)Ph₂ C₂₉H₂₁F₃NO₂PS 99.1 206-8 B16 p-CH(CH₃)₂ P(O)Ph₂ C₃₁H₂₅F₃NOPS 87.9 236-8 *: two steps' yield

TABLE 25 4,7-disubstituted thiophenyl-3-bromomethyl(or 3-diphenyl-phosphoryl-methyl)-quinoline (G17~20 or B17~20)

No R X Formula Yield % Mp ° C. G17 H Br C₂₂H₁₆BrNS₂ — — G18 p-F Br C₂₂H₁₄BrF₂NS₂ — — G19 m-OCH₃ Br C₂₄H₂₀BrNO₂S₂ — — G20 p-CH(CH₃)₂ Br C₂₈H₂₈BrNS₂  81.9  87-90 B17 H P(O)Ph₂ C₃₄H₂₆NOPS₂  71.6* 238-40 B18 p-F P(O)Ph₂ C₃₄H₂₄F₂NOPS₂  89.8* 213-5 B19 m-OCH₃ P(O)Ph₂ C₃₆H₃₀NO₃PS₂  87.8* 190-2 B20 p-CH(CH₃)₂ P(O)Ph₂ C₄₀H₃₈NOPS₂ 100 200-2 *: two steps' yield

TABLE 26 6-fluoro-4,7-disubstituted thiophenyl-3-bromomethyl(or 3-diphenyl- phosphoryl-methyl)-quinoline (G21~24 or B21~24)

No R X Formula Yield % Mp ° C. G21 H Br C₂₂H₁₅BrFNS₂ — 104 G22 p-F Br C₂₂H₁₃BrF₃NS₂ 89.8 150-2  G23 m-OCH₃ Br C₂₄H₁₉BrFNO₂S₂ — oil G24 p-CH(CH₃)₂ Br C₂₈H₂₇BrFNS₂ 74.2 145-7  B21 H P(O)Ph₂ C₃₄H₂₅FNOPS₂ 62.0* 238-41 B22 p-F P(O)Ph₂ C₃₄H₂₃F₃NOPS₂ 100 246-8  B23 m-OCH₃ P(O)Ph₂ C₃₆H₂₉FNO₃PS₂ 84.0* 229-30 B24 p-CH(CH₃)₂ P(O)Ph₂ C₄₀H₃₇FNOPS₂ 96.3 250-1  *two steps' yield

TABLE 27 6,8-difluoro-4,7-disubstituted thiophenyl-3-bromomethyl(or 3- diphenyl-phosphoryl-methyl)-quinoline (G25~28 or B25~28)

No R X Formula Yield % Mp ° C. G25 H Br C₂₂H₁₄BrF₂NS₂ 76.6 120-2 G26 p-F Br C₂₂H₁₂BrF₄NS₂ — — G27 m-OCH₃ Br C₂₄H₁₈BrF₂NO₂S₂ — — G28 p-CH(CH₃)₂ Br C₂₈H₂₆BrF₂NS₂ 80.3 116-7 B25 H P(O)Ph₂ C₃₄H₂₄F₂NOPS₂ 72.9 246-8 B26 p-F P(O)Ph₂ C₃₄H₂₂F₄NOPS₂ 72.4* 250-2 B27 m-OCH₃ P(O)Ph₂ C₃₆H₂₈F₂NO₃PS₂ 85.4* 184-5 B28 p-CH(CH₃)₂ P(O)Ph₂ C₄₀H₃₆F₂NOPS₂ 98.7  236-40 *two steps' yield

TABLE 28 4,6,7-trisubstituted thiophenyl-3-bromomethyl(or 3-diphenyl- phosphoryl-methyl)-quinoline (G29~32 or B29~32)

No R X Formula Yield % Mp ° C. G29 H Br C₂₈H₂₀BrNS₃ 88.9 140-2 G30 p-F Br C₂₈H₁₇BrF₃NS₃ 82.2 156-8 G31 m-OCH₃ Br C₃₁H₂₆BrNO₃S₃ — — G32 p-CH(CH₃)₂ Br C₃₇H₃₈BrNS₃ 69.3 104-7 B29 H P(O)Ph₂ C₄₀H₃₀NOPS₃ 94.2 246-8 B30 p-F P(O)Ph₂ C₄₀H₂₇F₃NOPS₃ 90.7 261-3 B31 m-OCH₃ P(O)Ph₂ C₄₃H₃₆NO₄PS₃ 82.1* 156-8 B32 p-CH(CH₃)₂ P(O)Ph₂ C₄₉H₄₈NOPS₃ 97.1 231-3 *two steps' yield

TABLE 29 6-fluoro-4,7,8-trisubstituted thiophenyl-3-bromomethyl(or 3-diphenyl-phosphoryl-methyl)-quinoline (G33~36 or B33~36)

Yield Mp No R X Formula % ° C. G33 H Br C₂₈H₁₉BrFNS₃ 86.7 150-2 G34 p-F Br C₂₈H₁₆BrF₄NS₃ 90.5 141-2 G35 m-OCH₃ Br C₃₁H₂₅BrFNO₃S₃ — — G36 p-CH(CH₃)₂ Br C₃₇H₃₇BrFNS₃ 82.0 135-8 B33 H P(O)Ph₂ C₄₀H₂₉FNOPS₃ 86.2  238-40 B34 p-F P(O)Ph₂ C₄₀H₂₆F₄NOPS₃ 100  229-31 B35 m-OCH₃ P(O)Ph₂ C43H35FNO4PS3 69.5*  178-80 B36 p-CH(CH₃)₂ P(O)Ph₂ C₄₉H₄₇FNOPS₃ 100 212-6 *two steps' yield

TABLE 30 4,6,7,8-tetrasubstituted thiophenyl-3-bromomethyl(or 3-diphenyl- phosphoryl-methyl)-quinoline (G37~40 or B37~40)

Yield Mp No R X Formula % ° C. G37 H Br C₃₄H₂₄BrNS₄ 100  139-41 G38 p-F Br C₃₄H₂₀BrF₄NS₄ 87.8 173-5 G39 m-OCH₃ Br C₃₈H₃₂BrNO₄S₄ — — G40 p-CH(CH₃)₂ Br C₄₆H₄₈BrNS₄ — Oil B37 H P(O)Ph₂ C₄₆H₃₄NOPS₄ 95.4 222-4 B38 p-F P(O)Ph₂ C₄₆H₃₀F₄NOPS₄ 82.8 225-7 B39 m-OCH₃ P(O)Ph₂ C₅₀H₄₂NO₅PS₄ 93.9* 104-6 B40 p-CH(CH₃)₂ P(O)Ph₂ C₅₈H₅₈NOPS₄ 78.8 160-4 *two steps' yield

TABLE 31 tert-butyl (3R, 5S, 6E)-7-(4-substituted thiophenylquinoline-3-yl]- 3,5-dihydroxy-3,5-O-isopropylidene-6-heptenoate (D1~4)

No R Formula [α]_(D) Yield* % Mp ° C. D1 H C₃₀H₃₆NO₄S −9.3, 29.6 135-6 c = 1, CH₂Cl₂ D2 p-F C₃₀H₃₅FNO₄S −9.4, 26.7 110-2 c = 1, CHCl₃ D3 m-OCH₃ C₃₁H₃₈NO₅S −3.4, 22.2 106-8 c = 1, CH₂Cl₂ T = 35° C. D4 p-CH(CH₃)₂ C₃₃H₄₂NO₄S +1.5  28.5 107-8 c = 0.68, Acetone *purified by silica gel chromatography (petroleum ether-EtOAc).

TABLE 32 ¹H-NMR data of D1~4 (δ ppm in CDCl₃) ¹H-NMR δ ppm in CDCl₃ No 2′H 8′H 5′H 6′H 7′H 7H

6H 5H 3H 2H 4H 2 × CH₃ & t-Bu D1 9.13 8.45 8.10 7.67 7.53 7.31 7.19-7.04 6.32 4.56- 4.32- 2.48- 1.62-1.24 (m, 17H) s d, d, t, t, d, (m, 5H) dd, 4.52 4.30 2.28 J = 8.0 J = 8.4 J = 7.6 J = 8.0 J = 16.0 J = 16.2, m m m 6.0 D2 9.10 8.45 8.10 7.70-7.66 7.57-7.52 7.30 7.08-7.05 6.30 4.57- 4.34- 2.49- 1.67-1.62 1.54-1.44 s dd, d, m m dd, (m, 2H), dd, 4.53 4.30 2.29 (m, 1H), (m, 15H) J = 8.6, J = 8.4 J = 16.2, 6.90-6.86 J = 16.4, m m m 1.34-1.25 1.2 0.8 (m, 2H) 6.4 (m, 1H) D3 9.14 8.43 8.10 7.68 7.53 7.21 7.08 6.34 4.59- 4.33- 2.48- 1.65-1.64 1.51-1.43 s d, d, t, t, d, (t, 1H, dd, 4.54 4.31 2.29 (m, 1H), (m, 15H) J = 8.0 J = 8.4 J = 6.8 J = 8.0 J = 16.0 J = 8.0) J = 16.4, m m m 1.35-1.27 6.66-6.59 6.0 (m, 1H) (m, 3H) 3.67 (s, 3H) D4 9.12 8.49-8.47 8.09 7.69-7.65 7.55-7.51 7.35 7.04-6.98 6.32 4.57- 4.34- 2.48- 1.67-1.62 1.51-1.44 s m d, m m d, (m, 4H) dd, 4.53 4.30 2.28 (m, 1H), (m, 15H) J = 8.0 J = 16.0 2.82-2.79 J = 16.2, m m m 1.36-1.28 (m, 1H), 6.4 (m, 1H) 1.18 (d, 6H, J = 7.2)

TABLE 33 (3R, 5S, 6E)-7-(7-fluoro-4-substituted thiophenylquinoline-3-yl]-3,5- dihydroxy-3,5-O-isopropylidene-6-heptenoate (D5~8)

Yield* Mp No R Formula [α]_(D) % ° C. D5 H C₃₀H₃₅ClNO₄S +4.9 31.9 130-2 c = 1, acetone D6 p-F C₃₀H₃₄ClFNO₄S +11.9  20.3 151-3 c = 1, acetone D7 m-OCH₃ C₃₁H₃₇ClNO₅S +7.8 25.0  96-8 c = 1, acetone D8 p-CH(CH₃)₂ C₃₃H₄₁ClNO₄S +1.9 33.6 oil c = 1, CH₂Cl₂

TABLE 34 ¹H-NMR data of D5~8 (δ ppm in CDCl₃) ¹H-NMR δ ppm in CDCl₃ No 2′H 5′H 8′H 6′H 7H

6H 5H 3H 2H 4H 2 × CH₃ & t-Bu D5 9.11 8.38 8.09 7.46 7.28 7.20-7.02 6.32 4.56-4.51 4.34-4.27 2.47-2.27 1.63-1.23 s d, d, dd, d, (m, 5H) dd, m m m m, 17H J = 9.2 J = 2.0 J = 8.8, J = 16.8 J = 16.4, 2.0 5.6 D6 9.09 8.39 8.09 7.50-7.47 7.26 7.08-7.04 6.30 4.57-4.53 4.35-4.29 2.49-2.29 1.67-1.24 s d, d, m d, (m, 2H) dd, m m m, 17H J = 8.8 J = 2.0 J = 16.4 6.92-6.87 J = 16.0, (m, 2H) 5.6 D7 9.12 8.36 8.09 7.46 7.28 7.10-7.06 6.33 4.58-4.53 4.33-4.30 2.48-2.28 1.65-1.25, s d, d, dd, dd, (m, 1H) dd, m m m m, 17H J = 9.2 J = 1.6 J = 9.2, J = 16.0, 6.68-6.58 J = 16.2, 2.4 0.8 (m, 3H) 6.0 3.68 (s, 3H) D8 9.09 8.38 8.06 7.45 7.30 7.04-6.95 (m, 4H) 6.30 4.56-4.52 4.32-4.29 2.46-2.27 1.65-1.22 s d, d, dd, d, 2.81-2.78 (m, 1H) dd, m m m m, 17H J = 8.8 J = 2.0 J = 9.0, J = 16.0 1.16 (d, 6H, J = 16.0, 1.6 J = 6.8) 5.6 *purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 35 (3R, 5S, 6E)-7-(7-fluoro-6-fluoro-4-substituted thiophenylquinoline- 3-yl]-3,5-dihydroxy-3,5-O-isopropylidene-6-heptenoate (D9~12)

Yield* Mp No R Formula [α]_(D) % ° C. D9 H C₃₀H₃₄ClFNO₄S −17. 7 46.5 131-3 c = 1, CHCl₃ D10 p-F C₃₀H₃₃ClF₂NO₄S +11.6 69.5 120-1 c = 1, acetone D11 m-OCH₃ C₃₁H₃₆ClFNO₅S −11.3 60.6  83-5 c = 1, CHCl₃ D12 p-CH(CH₃)₂ C₃₃H₄₀ClFNO₄S  +7.1 56.1 oil c = 1.1, acetone

TABLE 36 ¹H-NMR data of D9~12 (δ ppm in CDCl₃) ¹H-NMR δ ppm in CDCl₃ No 2′H 8′H 5′H 7H

6H 5H 3H 2H 4H, 2 × CH₃ & t-Bu D9 9.08 8.18-8.14 7.24 7.22-7.12 6.34 4.56-4.52 4.33-4.28 2.47-2.27 1.64-1.23 s m dd, (m, 3H) dd, m m m m, 17H J = 15.8, 1.2 7.05-7.03 J = 16.4, 5.6 (m, 2H) D10 9.06 8.18-8.16 7.28 7.09-7.05 6.33 4.57-4.53 4.34-4.31 2.49-2.29 1.67-1.26 s m d, (m, 2H) dd, m m m m, 17H J = 15.2 6.91-6.89 J = 16.4, 5.2 (m, 2H) D11 9.08 8.17-8.13 7.24 7.10 (t, 1H, J = 8.4) 6.35 4.58-4.54 4.33-4.29 2.48-2.28 1.66-1.24 s m dd, 6.70-6.58 dd, m m m m, 17H J = 17.2, 0.8 (m, 3H) J = 16.4, 6.0 3.69 (s, 3H) D12 9.07 8.18-8.14 7.31 7.06-6.97 (m, 4H) 6.35 4.58-4.54 4.33-4.31 2.48-2.28 1.66-1.24 s m d, 2.83-2.80 (m, 1H) dd, m m m m, 17H J = 16.4 1.18 (d, 6H, J = 6.8) J = 16.4, 5.6 *purified by silica gel chromatography (petroleum ether-EtOAc).

TABLE 37 (3R, 5S, 6E)-7-(6,7,8-trifluoro-4-substituted thiophenylquinoline-3-yl]-3,5- dihydroxy-3,5-O-isopropylidene-6-heptenoate (D13~16)

Yield* Mp No R Formula [α]_(D) % ° C. D13 H C₃₀H₃₃F₃NO₄S  +5.9 55.8  169-71 c = 1, acetone D14 p-F C₃₀H₃₂F₄NO₄S +15.4 70.8 126-8 c = 1, THF D15 m-OCH₃ C₃₁H₃₅F₃NO₅S +11.4 21.8 132-4 c = 1, acetone D16 p-CH(CH₃)₂ C₃₃H₃₉F₃NO₄S  +7.5 58.3  94-96 c = 0.32, acetone *purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 38 ¹H-NMR data of D13~16 (δ ppm in CDCl₃) ¹H-NMR δ ppm in CDCl₃ No 2′H 5′H 7H

6H 5H 3H 2H 4H 2 × CH₃ & t-Bu D13 9.11 8.07-8.04 7.29-7.15 (m, 4H), 6.34 4.56-4.52 4.32-4.29 2.47-2.27 1.64-1.21 s m 7.05-7.03 (m, 2H) dd, m m m m, 17H J = 16.8, 6.0 D14 9.07 8.07-8.02 7.24 7.07-7.04 (m, 2H), 6.30 4.56-4.52 4.33-4.28 2.47-2.27 1.66-1.19, s m d, 6.93-6.88 (m, 2H) dd, m m m m, 17H J = 16.0 J = 16.0, 5.6 D15 9.11 8.06-8.00 7.27 7.10 (t, 1H, J = 8.0) 6.36 4.58-4.54 4.34-4.28 2.48-2.28 1.66-1.23, s m d, 6.71-6.58 (m, 1H), dd, m m m m, 17H J = 16.0 6.60-6.58 (m, 2H) J = 16.4, 5.6 3.70 (s, 3H) D16 9.11 8.09-8.04 7.31 7.08-6.98 (m, 4H) 6.34 4.58-4.54 4.33-4.30 2.48-2.28 1.68-1.25 s m dd, 2.84-2.81 (m, 1H) dd, m m m m, 17H J = 16.4, 1.2 1.19 (d, 6H, J = 6.8) J = 16.0, 5.6

TABLE 39 (3R, 5S, 6E)-7-(4,7-disubstituted thiophenylquinoline-3-yl]-3,5-dihydroxy-3,5-O- isopropylidene-6-heptenoate (D17~20)

No R Formula [α]_(D) Yield* % Mp ° C. D17 H C₃₆H₄₀NO₄S₂ +0.8 26.2  109-10 c = 1, THF D18 p-F C₃₆H₃₈F₂NO₄S₂ +6.4 45.7 155-7 c = 0.7, acetone D19 m-OCH₃ C₃₈H₄₄NO₆S₂ −3.6 52.8 oil c = 1, CH₂Cl₂ D20 p-CH(CH₃)₂ C₄₂H₅₂NO₄S₂ −10.2  21.7 107-8 c = 0.84, CH₂Cl₂ *purified by silica gel chromatography (petroleum ether-EtOAc).

TABLE 40 ¹H-NMR data of D17~20 (δ ppm in CDCl₃) ¹H-NMR δ ppm in CDCl₃ No 2′H 5′H 8′H 6′H 7H

6H 5H 3H 2H 4H 2 × CH₃ & t-Bu D17 9.05 8.32 7.81 7.54 7.39-7.36 (m, 4H) 6.29 4.55-4.51 4.32-4.29 2.47-2.28 1.62-1.24 s d, d, dd, 7.29-7.25 (m, 2H) dd, m m m m, 17H J = 9.2 J = 1.6 J = 6.6, 7.19-7.03 (m, 5H) J = 16.2, 1.6 6.0 D18 9.01 8.32 7.70 7.34 7.24 7.56-7.52 (m, 2H) 6.26 4.55-4.51 4.32-4.29 2.48-2.28 1.65-1.23 s d, d, dd, d, 7.12-7.02 (m, 4H) dd, m m m m, 17H J = 8.8 J = 1.6 J = 10.0, J = 16.4 6.90-6.86 (m, 2H) J = 16.4, 1.6 6.0 D19 9.05 8.30 7.84 7.46 7.30-7.24 (m, 2H) 6.30 4.56-4.52 4.32-4.29 2.47-2.27 1.64-1.25, s d, d, dd, 7.11-7.05 (m, 3H) dd, m m m m, 17H J = 8.8 J = 1.2 J = 9.0, 6.91-6.88 (m, 1H), J = 16.0, 2.0 6.66-6.59 (m, 3H) 5.6 3.77 (s, 3H), 3.67 (s, 3H) D20 9.05 8.36 7.77 7.38 7.51-7.49 (m, 2H), 6.30 4.58-4.54 4.35-4.32 2.49-2.30 1.67-1.35 s d, d, dd, 7.30-7.28 (m, 3H) dd, m m m m, 17H J = 8.8 J = 1.6 J = 9.0, 7.07-7.00 (m, 4H) J = 16.2, 1.6 2.98-2.95 (m, 1H) 5.6 2.85-2.82 (m, 1H) 1.31 (d, 6H, J = 6.8) 1.21 (d, 6H, J = 7.2)

TABLE 41 (3R, 5S, 6E)-7-(6-fluoro-4,7-disubstituted thiophenylquinoline-3-yl]-3,5-dihydroxy-3,5-O- isopropylidene-6-heptenoate (D21~24)

Yield* Mp No R Formula [α]_(D) % ° C. D21 H C₃₆H₃₉FNO₄S₂ +1.2 67.4 oil c = 1, acetone D22 p-F C₃₆H₃₇F₃NO₄S₂ +5.3 35.6 106-8 c = 0.88, acetone D23 m-OCH₃ C₃₈H₄₃FNO₆S₂ −2.4 59.3 123-5 c = 1, acetone D24 p-CH(CH₃)₂ C₄₂H₅₁FNO₄S₂ −6.1 45.4  94-5 c = 1., CH₂Cl₂ *purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 42 ¹H-NMR data of D21~24 (δ ppm in CDCl₃) ¹H-NMR δ ppm in CDCl₃ No 2′H 5′H 8′H 7H

6H 5H 3H 2H 4H 2 × CH₃ & t-Bu D21 8.97 8.05 7.60 7.23 7.58-7.55 (m, 2H), 6.29 4.55-4.50 4.31-4.28 2.47-2.26 1.62-1.20 s d, d, dd, 7.44-7.40 (m, 3H), dd, m m m m, 17H J = 10.8 J = 7.2 J = 16.4, 7.21-7.11 (m, 3H), J = 16.4, 1.2 7.05-7.03 (m, 2H) 6.0 D22 8.94 8.05 7.59-7.50 (m, 3H), 7.25-7.04 (m, 5H), 6.27 4.55-4.51 4.32-4.29 2.48-2.28 1.65-1.25 s d, 6.93-6.88 (m, 2H) dd, m m m m, 17H J = 11.2 J = 16.4, 5.6 D23 8.98 8.04 7.65 7.35-7.30 (m, 1H), 7.27-7.23 6.30 4.56-4.52 4.32-4.29 2.47-2.27 1.63-1.20 s d, d, (m, 1H), 7.14-7.07 (m, 3H), dd, m m m m, 17H J = 11.2 J = 7.6 6.96-6.93 (m, 1H), 6.68-6.59 J = 16.0, (m, 3H), 3,79 (s, 3H), 3.69 (s, 3H) 5.6 D24 8.95 8.05 7.53-7.49 (m, 3H), 7.30-7.25 (m, 3H), 6.33 4.55-4.51 4.31-4.27 2.46-2.26 1.64-1.41 s d, 7.05-6.96 (m, 4H), 2.96-2.93 (m, 1H), dd, m m m m, 17H J = 11.6 2.82-2.79 (m, 1H), 1.28 (d, 6H, J = 6.8), J = 16.0, 1.17 (d, 6H, J = 7.2) 5.6

TABLE 43 (3R, 5S, 6E)-7-(6,8-difluoro-4,7-disubstituted thiophenylquinoline-3-yl]-3,5-dihydroxy-3,5-O-isopropylidene- 6-heptenoate (D25~28)

Yield* Mp No R Formula [α]_(D) % ° C. D25 H C₃₆H₃₈F₂NO₄S₂ −1.8 20.5 178- c = 1, 80 CH₂Cl₂ D26 p-F C₃₆H₃₆F₄NO₄S₂ +7.6 47.5 167- c = 1, 70 CH₂Cl₂ D27 m-OCH₃ C₃₈H₄₂F₂NO₆S₂ +9.7 52.9 119- c = 0.78, 21 acetone D28 p-CH(CH₃)₂ C₄₂H₅₀F₂NO₄S₂ +10.4  42.6 107-8 c = 1, THF *purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 44 ¹H-NMR data of D25~28 (δ ppm in CDCl₃) ¹H-NMR δ ppm in CDCl₃ No 2′H 5′H 7H

6H 5H 3H 2H 4H 2 × CH₃ & t-Bu D25 9.09 7.97 7.39-7.37 (m, 3H), 7.29-7.15 (m, 6H) 6.36 4.56-4.53 4.31-4.29 2.47-2.27 1.62-1.23 s dd 7.07-7.05 (m, 2H) dd, m m m m, 17H J = 10.0, 1.2 J = 16.4, 5.6 D26 9.03 7.96 7.25 7.47-7.43 (m, 2H) 6.34 4.57-4.53 4.33-4.30 2.49-2.28 1.67-1.23 s dd dd, 7.09-7.06 (m, 2H) dd, m m m m, 17H J = 10.4, 2.0 J = 16.4, 1.2 6.99-6.89 (m, 4H) J = 16.0, 5.6 D27 9.10 7.95 7.27 7.17-7.09 (m, 2H), 6.38 4.58-4.54 4.32-4.29 2.47-2.28 1.65-1.22, s dd d, 6.93-6.89 (m, 2H) dd, m m m m, 17H J = 10.4, 2.0 J = 16.0 6.76-6.60 (m, 4H) J = 16.4, 5.6 3.73 (s, 3H), 3.69 (s, 3H) D28 9.08 7.98 7.36-7.29 (m, 3H), 7.13-6.99 (m, 6H), 6.36 4.58-4.54 4.34-4.30 2.48-2.28 1.68-1.25 s dd 2.87-2.81 (m, 2H), 1.22-1.19 (m, 12H) dd, m m m m, 17H J = 10.0, 1.2 J = 16.0, 5.6

TABLE 45 (3R, 5S, 6E)-7-(4,7,6-trisubstituted thiophenylquinoline-3-yl]-3,5-dihydroxy-3,5-O-isopropylidene- 6-heptenoate (D29~32)

Yield* Mp No R Formula [α]_(D) % ° C. D29 H C₄₂H₄₄NO₄S₃ −10.2  80.4 138- c = 1.0 40 CH₂Cl₂ D30 p-F C₄₂H₄₁F₃NO₄S₃ +4.2 29.4 158- c = 1, 60 acetone D31 m-OCH₃ C₄₅H₅₀NO₇S₃ −7.6 58.6 oil c = 1.04 CH₂Cl₂ D32 p-CH(CH₃)₂ C₅₁H₆₂NO₄S₃ −8.3 36.6 110-1 c = 0.86 CH₂Cl₂ *purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 46 ¹H-NMR data of D29~32 (δ ppm in CDCl₃) ¹H-NMR δ ppm in CDCl₃ No 2′H 5′H 8′H 7H

6H 5H 3H 2H 4H 2 × CH₃ & t-Bu D29 8.95 8.13 7.57 7.54-7.52 (m, 2H), 7.43-7.39 (m, 3H), 6.27 4.55-4.50 4.31-4.28 2.46-2.26 1.64-1.25 s s s 7.32-7.24 (m, 6H), 7.14-7.09 (m, 3H), dd, m m m m, 17H 6.86-6.84 (m, 2H) J = 16.0, 5.6 D30 8.95 7.98 7.50 7.56-7.51 (m, 2H), 7.36-7.32 (m, 2H), 6.29 4.57-4.53 4.33-4.30 2.48-2.28 1.69-1.28 s s s 7.28-7.23 (m, 3H), 7.15-7.11 (m, 2H), dd, m m m m, 17H 7.04-7.00 (m, 2H), 6.86-6.84 (m, 2H) J = 16.0, 5.6 D31 8.96 8.18 7.63 7.33-6.82 (m, 10H), 6.63-6.60 (m, 1H), 6.28 4.55-4.51 4.31-4.28 2.46-2.27 1.64-1.22 s s s 6.44-6.40 (m, 2H), 3.77 (s, 3H), 3.70 dd, m m m m, 17H (s, 3H), 3.65 (s, 3H) J = 16.4, 6.0 D32 8.91 8.04 7.53 7.49 (d, 2H, J = 8.0),7.32-7.25 (m, 5H), 6.25 4.56-4.52 4.32-4.29 2.46-2.27 1.66-1.34 s s s 7.19 (d, 2H, J = 8.4), 6.99 (d, 2H, J = 8.8), dd, m m m m, 17H 6.76 (d, 2H, J = 8.0), 2.98-2.91 (m, 2H), J = 16.0, 2.82-2.46 (m, 1H), 1.31-1.19 (m, 18H) 5.6

TABLE 47 (3R, 5S, 6E)-7-(6-fluoro-4,7,8-trisubstituted thiophenylquinoline-3-yl]-3,5-dihydroxy-3,5-O-isopropylidene- 6-heptenoate (D33~36)

Yield* Mp No R Formula [α]_(D) % ° C. D33 H C₃₄H₂₆FNO₃S₃ −0.8 59.2  159- c = 1, 61 CH₂Cl₂ D34 p-F C₄₂H₄₀F₄NO₄S₃ +9.2 60.2 194-6 c = 1, acetone D35 m-OCH₃ C₄₅H₄₉FNO₇S₃ +10.0  80.0 oil c = 1, acetone D36 p-CH(CH₃)₂ C₅₁H₆₁FNO₄S₃ +2.9 57.3 111-2 c = 1, acetone *purified by silica gel chromatography (petroleum ether-EtOAc).

TABLE 48 ¹H-NMR data of D33~36 (δ ppm in CDCl₃) ¹H-NMR δ ppm in CDCl₃ No 2′H 5′H 7H

6H 5H 3H 2H 4H 2 × CH₃ & t-Bu D33 9.13 8.19 7.27-7.06 (m, 16H) 6.33 4.54-4.50 4.32-4.28 2.47-2.27 1.61-1.18 s d dd, m m m m, 17H J = 10.8 J = 16.0, 5.6 D34 9.10 8.17 7.27-7.19 (m, 5H), 6.31 4.54-4.53 4.33-4.29 2.48-2.28 1.65-1.19 s d, 7.10-7.05 (m, 2H), dd, m m m m, 17H J = 10.4 6.94-6.86 (m, 6H) J = 16.0, 5.2 D35 9.13 8.18 7.25 7.13-7.03 (m, 3H), 6.44 4.56-4.52 4.31-4.28 2.47-2.27 1.64-1.20, s d, dd, 6.80-6.58 (m, 9H), dd, m m m m, 17H J = 10.4 J = 16.4, 3.70-3.67 (m, 9H) J = 16.4, 1.2 6.0 D36 9.13 8.17 7.28 7.13 (t, 4H, J = 8.4) 6.32 4.56-4.51 4.32-4.29 2.47-2.27 1.65-1.22 s d, d, 7.07-6.99 (m, 8H) dd, m m m m, 17H J = 10.4 J = 16.0 2.86-2.79 (m, 3H) J = 16.4, 1.20-1.18 (m, 18H) 6.0

TABLE 49 (3R, 5S, 6E)-7-(4,6,7,8-tetrasubstituted thiophenylquinoline-3-yl]-3,5-dihydroxy-3,5-O-isopropylidene- 6-heptenoate (D37~40)

Yield* Mp No R Formula [α]_(D) % ° C. D37 H C₄₈H₄₈NO₄S₄ +2.7 38.1 160-2 c = 1, THF D38 p-F C₄₈H₄₄F₄NO₄S₄ +8.4 35.5  169- c = 1, 71 acetone D39 m-OCH₃ C₅₂H₅₆NO₈S₄ +10.4  76.7 oil c = 1, acetone D40 p-CH(CH₃)₂ C₆₀H₇₂NO₄S₄ +6.9 70.9 144-6 c = 1, acetone *purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 50 ¹H-NMR data of D37~40 (δ ppm in CDCl₃) ¹H-NMR δ ppm in CDCl₃ No 2′H 5′H 7H

6H 5H 3H 2H 4H 2 × CH₃ & t-Bu D37 9.00 7.87 7.42-7.02 (m, 19H), 6.28 4.54-4.49  4.30-4.287 2.46-2.26 1.63-1.22 s s 6.74-6.72 (m, 2H) dd, m m m m, 17H J = 16.4, 6.0 D38 8.99 7.71 7.40-7.37 (m, 2H), 7.25-7.03 (m, 6H), 6.30 4.56-4.52 4.31-4.28 2.47-2.27 1.67-1.24 s s 6.93-6.79 (m, 7H), 6.73-6.69 (m, 2H) dd, m m m m, 17H J = 16.4, 6.0 D39 8.94 8.03 7.39-7.29 (m, 3H), 7.17-6.96 (m, 6H), 6.32 4.65-4.61 4.36-4.33 2.50-2.31 1.77-1.23, s s 6.75-6.55 (m, 8H), 3.80-3.63 (m, 9H), dd, m m m m, 17H 2.07 (s, 3H) J = 16.4, 5.6 D40 8.99 7.84 7.32-7.21 (m, 6H), 7.14-7.11 (m, 2H), 6.28 4.54-4.52 4.31-4.28 2.47-2.27 1.65-1.34. s s 7.05-6.94 (m, 7H), 6.67-6.65 (m, 2H), dd, m m m m, 17H 2.97-2.94 (m, 1H), 2.85-2.76 (m, 3H), J = 16.0, 1.30-1.14 (m, 24H) 6.0

TABLE 51 (4R, 6S)-6-[(E)-2-(4-substituted thiophenylquinoline-3-yl)-ethenyl]- 3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (A1~4)

No R Formula [α]_(D) Yield* (%) Mp (° C.) MS EI⁺ (M + 1) A1 H C₂₂H₁₉NO₃S +26.7, c = 0.94, CH₂Cl₂ 91.7 102-4 378 A2 p-F C₂₂H₁₈FNO₃S +28.9, c = 0.47, CH₂Cl₂ 82.2 130-2 396 A3 m-OCH₃ C₂₃H₂₁NO₄S +24.2, c = 0.88, CH₂Cl₂ 95.6 132-5 408 A4 p-CH(CH₃)₂ C₂₅H₂₅NO₃S +28.9, c = 0.84, CH₂Cl₂ 37.8 147-8 420 *purified by silica gel chromatography (petroleum ether-EtOAc).

TABLE 52 ¹H-NMR data of A1~4 (δ ppm in CDCl₃) No 2″H 8″H 5″H 6″H 7″H 2′H

1′H 6H 4H 3H 5H A1 9.29 8.38 8.09 7.80-7.75 7.67-7.63 7.32, 7.24 (t, 2H, 6.75, 5.31-5.26 4.15-4.12 2.71-2.42 1.95-1.77 s d, d, m m dd, J = 7.6), dd, m m m m J = 8.4 J = 7.6 J = 16.4, 7.17 (t, 1H, J = 16.0, 1.2 J = 7.2) 6.0 7.08-7.06 (m, 2H) A2 9.08 8.46, 8.11, 7.73-7.69 7.76, t, 7.40, 7.08-7.04 6.34, 5.38-5.34 4.42-4.39 2.80-2.63 2.07-1.83 s d, d, m J = 7.2 dd, (m, 2H), dd, m m m m J = 8.0 J = 8.4 J = 16.2, 6.91-6.87 (m, J = 16.0, 1.2 2H) 6.0 A3 9.09 8.47, 8.11, 7.71, t, 7.56, t, 7.37, d, 7.07 (t, 1H, 6.34, 5.36-5.33 4.35-4.33 2.77-2.61 2.03-1.82 s d, d, J = 7.6 J = 8.0 J = 16.4 J = 8.0), dd, m m m m J = 8.4 J = 8.8 6.67-6.57 (m, J = 16.2, 3H), 3.68 (s, 5.6 3H) A4 9.09 8.51, 8.12, 7.71, t, 7.56, t, 7.41, d, 7.06-7.00 (m, 6.33, 5.34 4.36 2.72-2.63 2.02-1.82 s d, d, J = 8.0 J = 8.0 J = 16.8 4H), dd, s s m m J = 8.4 J = 8.0 2.85-2.74 (m, J = 16.4, 1H), 6.0 1.18 (d, 6H, J = 6.8)

TABLE 53 (4R, 6S)-6-[(E)-2-(7-chloro-4-substituted thiophenylquinoline-3-yl)-ethenyl]- 3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (A5~8)

No R Formula [α]_(D) Yield* (%) Mp (° C.) MS EI⁺ (M + 1) A5 H C₂₂H₁₈ClNO₃S +25.0, c = 1, CH₂Cl₂ 48.7 158-9 412 A6 p-F C₂₂H₁₇ClFNO₃S +21.1, c = 1, CH₂Cl₂ 48.7  179-81 430 A7 m-OCH₃ C₂₃H₂₀ClNO₄S +22.3, c = 1, CH₂Cl₂ 57.5 140-2 442 A8 p-CH(CH₃)₂ C₂₅H₂₄ClNO₃S +14.1, c = 1, CH₂Cl₂ 41.0 170 454 *purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 54 ¹H-NMR data of A5~8 (δ ppm in CDCl₃) No 2″H 5″H 8″H 6″H 2′H

1′H 6H 4H 3H 5H A5 9.07 8.38, 8.09, 7.48, 7.34, 7.20-7.01 (m, 5H) 6.34, dd, 5.37-5.32 4.37-4.33 2.76-2.62 2.05-1.78 s d, d, dd, dd, J = 16.4, m m m m J = 9.2 J = 2.0 J = 9.2, J = 16.4, 6.0 2.4 1.6 A6 9.06 8.38, 8.09, 7.50, 7.37, 7.07-7.03 (m, 2H) 6.34, dd, 5.39-5.34 4.42-4.38 2.79-2.64 2.09-1.81 s d, d, dd, dd, 6.93-6.88 (m, 2H) J = 15.8, m m m m J = 8.8 J = 2.0 J = 9.2, J = 16.0, 5.6 2.0 0.8 A7 9.07 8.38, 8.09, 7.49, 7.34, 7.08 (t, 1H, J = 8.0) 6.34, dd, 5.37-5.32 4.34-4.32 2.76-2.62 2.05-1.79 s d, d dd, dd, 6.68-6.55 (m, 3H), J = 16.4, m m m m J = 9.2 J = 1.6 J = 9.2, J = 16.0, 3.69 (s, 3H) 6.0 2.0 0.8 A8 9.07 8.42, 8.10, 7.49, 7.37, 7.06-6.96 (m, 4H), 6.33, dd, 5.36-5.32 4.38-4.35 2.78-2.62 2.04-1.79 s d, d, dd, dd, 2.85-2.80 (m, 1H) J = 16.4, m m m m J = 8.8 J = 2.0 J = 8.8, J = 16.0, 1.18 (d, 6H, J = 6.8) 6.0 2.0 0.8

TABLE 55 (4R, 6S)-6-[(E)-2-(7-chloro-6-fluoro-4-substituted thiophenylquinoline-3-yl)-ethenyl]- 3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one (A9~12)

No R Formula [α]_(D) Yield* (%) Mp (° C.) MS EI⁺ (M + 1) A9 H C₂₂H₁₇ClFNO₃S +18.3, c = 1, CHCl₃  63.0 172-4 430 A10 p-F C₂₂H₁₆ClF₂NO₃S +25.1, c = 1, CH₂Cl₂ 75.0 192-4 448 A11 m-OCH₃ C₂₃H₁₉ClFNO₄S +21.1, c = 1, CH₂Cl₂ 62.2 150-3 460 A12 p-CH(CH₃)₂ C₂₅H₂₃ClFNO₃S +16.2, c = 1, CH₂Cl₂ 63.7 175-7 472 *purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 56 ¹H-NMR data of A9~12 (δ ppm in CDCl₃) No 2″H 8″H 5″H 2′H

1′H 6H 4H 3H 5H A9  9.05 s 8.19-8.15 m 7.35, dd, 7.22-7.15(m, 3H), 6.36, dd, 5.37-5.32 m 4.37-4.33 m 2.77-2.61 m 2.05-1.79 m J = 16.0, 1.2 7.05-7.02(m, 2H)  J = 16.2, 6.0 A10 9.03 s 8.19-8.15 m 7.37, dd, 7.08-7.03(m, 2H), 6.36, dd, 5.39-5.35 m 4.42-4.40 m 2.79-2.64 m 2.09-1.80 m J = 16.6, 0.8 6.95-6.90(m, 2H)  J = 16.2, 5.6 A11 9.04 s 8.19-8.15 m 7.34, dd, 7.10(t, 1H, J = 8.0), 6.36, dd, 5.37-5.33 m 4.37-4.33 m 2.77-2.61 m 2.05-1.80 m J = 16.4, 1.2 6.70-6.67(m, 1H), J = 16.2, 5.6 6.61-6.56(m, 2H), 3.71(s, 3H) A12 9.02 s 8.19-8.15 m 7.37, d, 7.06(d, 2H, J = 8.4), 6.35, dd, 5.38-5.33 m 4.39-4.36 m 2.72-2.62 m 2.04-1.78 m J = 16.8 6.96(d, 2H, J = 8.8)  J = 16.4, 6.0 2.85-2.78(m, 1H), 1.18(d, 6H, J = 7.2) 

TABLE 57 (4R,6S)-6-[(E)-2-(6,7,8-trifluoro-4- substitutedthiophenylquinoline-3-yl)-ethenyl]- 3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one(A13~16)

Yield* Mp MS EI⁺ No R Formula [α]_(D) (%) (° C.) (M + 1) A13 H C₂₂H₁₆F₃NO₃S +27.7, 81.4 177-8 432 c = 1, CH₂Cl₂ A14 p-F C₂₂H₁₅F₄NO₃S +26.2, 50.9 183-5  450 c = 1, CH₂Cl₂ A15 m-OCH₃ C₂₃H₁₅F₃NO₄S +25.5, 54.7 168-70 462 c = 0.6, CH₂Cl₂ A16 p-CH(CH₃)₂ C₂₅H₂₂F₃NO₃S +18.7, 62.0 169-71 474 c = 1, CH₂Cl₂ *: purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 58 ¹H-NMR data of A13~16 (δ ppm in CDCl₃) No 2″H 5″H 2′H

1′H 6H 4H 3H 5H A13 9.08 s 8.08-8.03 m 7.35, dd, 7.23-7.14(m, 3H)  6.36, dd, 5.37-5.32 m 4.37-4.35 m 2.76-2.62 m 2.05-1.77 m J = 16.4, 1.6 7.04-7.02(m, 2H)  J = 16.0, 5.6 A14 9.07 s 8.08-8.03 m 7.36, d, 7.09-7.05(m, 2H)  6.36, dd, 5.40-5.35 m 4.41 s 2.79-2.65 m 2.08-1.79 m J = 16.4 6.95-6.91(m, 2H)  J = 16.4, 6.0 A15 9.08 s 8.08-8.03 m 7.33, dd, 7.11(t, 1H, J = 8.0) 6.36, dd, 5.38-5.33 m 4.37-4.35 m 2.77-2.62 m 2.06-1.79 m J = 16.0, 1.2 6.72-6.55(m, 3H), J = 16.4, 6.0 3.71(s, 3H) A16 9.08 s 8.11-8.06 m 7.37, d, 7.09-7.00(m, 4H), 6.35, dd, 5.37-5.32 m 4.39-4.36 m 2.78-2.62 m 2.03-2.78 m J = 16.4 2.86-2.79(m, 1H), J = 16.0, 5.6 1.22-1.18(m, 6H) 

TABLE 59 (4R,6S)-6-[(E)-2-(4,7-disubstituted thiophenylquinoline-3-yl)-ethenyl]-3,4,5,6- tetrahydro-4-hydroxy-2H-pyran-2-one(A17~20)

MS Yield* Mp EI⁺ No R Formula [α]_(D) (%) (° C.) (M + 1) A17 H C₂₈H₂₃NO₃S₂ +17.8, 64.6 138- 486 c = 0.8, 40 CH₂Cl₂ A18 p-F C₃₀H₂₇NO₅S₂ +12.2, 75.9 140- 522 c = 0.97,  2 CH₂Cl₂ A19 m-OCH₃ C₃₀H₂₇NO₅S₂ +15.9, 52.8  48- 546 c = 1, 51 CH₂Cl₂ A20 p- C₃₄H₃₅NO₃S₂ +7.4, 66.5 109- 570 CH(CH₃)₂ c = 1, 12 CH₂Cl₂ *: purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 60 ¹H-NMR data of A17~20 (δ ppm in CDCl₃) No 2″H 5″H 8″H 6″H 2′H

1′H 6H 4H 3H 5H A17 9.00 s 8.32, d, 7.80 s 7.55-7.52 m 7.41-7.31(m, 6H), 6.29, dd, 5.33-5.29 m 4.33-4.31 m 2.75-2.59 m 2.01-1.78 m J = 8.8 7.19-7.01(m, 5H)  J = 16.2, 6.4 A18 9.00 s 8.31, d, 7.69, d, 7.56-7.53(m, 2H), 6.29, dd, 5.36-5.32 m 4.38 s 2.78-2.62 m 2.08-1.80 m J = 9.2 J = 1.6 7.36-7.32(m, 2H), J = 16.2, 6.4 7.13-7.19(m, 2H), 7.05-7.02(m, 2H), 6.91-6.86(m, 2H)  A19 9.01 s 8.33, d, 7.84, d, 7.40, dd, 7.34-7.26(m, 2H), 6.30, dd, 5.35- 5.30 m 4.34-4.32 m 2.76-2.60 m 2.03-1.80 m J = 8.8 J = 2.0 J = 8.8, 2.0 7.12-7.05(m, 3H), J = 16.2, 6.0 6.93-6.90(m, 1H), 6.68-6.56(m, 3H), 3.78(s, 3H), 3.69(s, 3H) A20 9.01 s 8.37, d, 7.78, d, 7.40, dd, 7.51(d, 2H, J = 8.4), 6.31, dd, 5.35-5.32 m 4.37 s 2.79-2.62 m 2.03-1.82 m J = 8.8 J = 1.6 J = 6.6, 2.0 7.35-7.28(m, 3H), J = 16.2, 6.0 7.08-6.98(m, 4H), 2.99-2.95(m, 1H), 2.85-2.80(m, 1H), 1.31(d, 6H, J = 7.2), 1.20(d, 6H, J = 7.2) 

TABLE 61 (4R,6S)-6-[(E)-2-(6-fluoro-4,7-disubstituted thiophenylquinoline-3-yl)-ethenyl]-3,4,5,6- tetrahydro-4-hydroxy-2H-pyran-2-one(A21~24)

MS Yield* Mp EI⁺ No R Formula [α]_(D) (%) (° C.) (M + 1) A21 H C₂₈H₂₂FNO₃S₂ +8.0, 82.2 92-4 504 c = 0.8, CH₂Cl₂ A22 p-F C₂₈H₂₀F₃NO₃S₂ +2.4, 67.0 128-30 540 c = 1, CH₂ Cl₂ A23 m-OCH₃ C₃₀H₂₆FNO₅S₂ +6.0, 67.9 133-4  564 c = 1, CH₂Cl₂ A24 p- C₃₄H₃₄FNO₃S₂ +2.9, 45.8 134-6  588 CH(CH₃)₂ c = 1, CH₂Cl₂ *: purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 62 ¹H-NMR data of A21~24 (δ ppm in CDCl₃) No 2″H 8″H 5″H 2′H

1′H 6H 4H 3H 5H A21 8.93 s 8.06, d, 7.60-7.56(m, 3H), 7.45-7.42(m, 3H), 6.30, dd, 5.34- 5.29 m 4.33-4.31 m 2.74-2.59 m 2.05-1.77 m J = 11.2 7.32(dd, 1H, J = 16.8, 1.6), J = 16.4, 6.0 7.21-7.11(m, 3H), 7.04-7.01(m, 2H)  A22 8.92 s 8.04, d, 7.49, d, 7.33, dd, 7.60-7.56(m, 2H), 6.30, dd, 5.36-5.32 m 4.38-4.36 m 2.77-2.67 m 2.05-1.79 m J = 11.2 J = 7 .6 J = 16.0, 0.8 7.17-7.13(m, 2H)  J = 16.0, 5.6 7.07-7.03(m, 2H), 6.93-6.88(m, 2H)  A23 8.93 s 8.06, d, 7.36-7.29(m, 2H), 7.16-7.07(m, 3H), 6.30, dd, 5.34-5.30 m 4.33-4.31 m 2.75-2.59 m 2.02-1.79 m J = 11.2 6.98-6.95(m, 1H), J = 16.0, 5.6 6.69-6.67(m, 1H), 6.60-6.56(m, 2H), 3.80(s, 3H), 3.70(s, 3H) A24 8.91 s 8.06, d 7.55-7.50(m, 3H), 7.36-7.25(m, 3H), 6.29, dd, 5.34- 5.29 m 4.35-4.33 m 2.75-2.59 m 2.03-1.78 m J = 11.2 7.07-6.95(m, 4H), 3.00-2.93(m, 1H), J = 16.4, 6.4 2.85-2.78(m, 1H), 1.30(d, 6H, J = 6.4), 1.18(d, 6H, J = 6.4),

TABLE 63 (4R,6S)-6-[(E)-2-(6,8-difluoro-4,7-disubstituted thiophenylquinoline- 3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one(A25~28)

Yield* Mp MS EI⁺ No R Formula [α]_(D) (%) (°C.) (M + 1) A25 H C₂₈H₂₁F₂NO₃S₂ +23.7, 59.8 186-8 522 c = 1, CH₂Cl₂ A26 p-F C₂₈H₁₉F₄NO₃S₂ +20.4, 64.2 156-8 558 c = 1, CH₂Cl₂ A27 m-OCH₃ C₃₀H₂₅F₂NO₅S₂ +21.4, 53.2 140-2 582 c = 1, CH₂Cl₂ A28 p-CH(CH₃)₂ C₃₄H₃₃F₂NO₃S₂ +17.4, 96.8 145-7 606 c = 1, CH₂Cl₂ *: purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 64 ¹H-NMR data of A25~28 (δ ppm in CDCl₃) No 2″H 5″H 2′H

1′H 6H 4H 3H 5H A25 9.06 s 7.98, dd 7.39-7.32(m, 3H), 7.28-7.14(m, 6H), 6.38, dd, 5.37-5.32 m 4.36-4.34 m 2.76-2.61 m 2.06-1.76 m J = 10.0, 1.2 7.06-7.04(m, 2H) J = 16.0, 5.6 A26 9.04 s 7.95, dd 7.35, dd, 7.47-7.44(m, 2H), 7.09-7.05(m, 2H), 7.37, dd, 5.39-5.34 m 4.40-4.39 m 2.78-2.64 m 2.08-1.78 m J=10.0, 2.0 J = 16.4, 1.2 7.00-6.90(m, 4H) J = 16.4, 5.6 A27 9.06 s 7.97, dd 7.33, d,  7.18-7.08(m, 2H), 6.93-6.90(m, 2H), 6.38, dd, 5.37-5.34 m 4.36-4.34 m 2.76-2.61 m 2.04-1.77 m J = 10.0, 0.8 J = 16.0 6.77-6.57(m, 4H), 3.74(s, 3H), J = 16.4, 5.6 3.68(s, 3H) A28 9.04 s 7.99, dd 7.38-7.34(m, 3H), 7.13-7.06(m, 4H) 6.36, dd, 5.35-5.32 m 4.36-4.35 m 2.77-2.61 m 2.02-1.78 m J = 10.4, 1.2 6.99-6.97(m, 2H), 2.87-2.80(m, 2H), J = 16.4, 6.0 1.21-1.17(m, 6H)

TABLE 65 (4R,6S)-6-[(E)-2-(4,6,7-trisubstituted thiophenylquinoline-3-yl)- ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one(A29~32)

Yield* Mp MS EI⁺ No R Formula [α]_(D) (%) (° C.) (M + 1) A29 H C₃₄H₂₇NO₃S₃ +19.7, 81.5 190-2 594 c = 1, CH₂Cl₂ A30 p-F C₃₄H₂₄F₃NO₃S₃ +18.0, 84.2 180-1 648 c = 1, CH₂Cl₂ A31 m-OCH₃ C₃₇H₃₃NO₆S₃ +21.4, 67.7  57-59 684 c = 1, CH₂Cl₂ A32 p-CH(CH₃)₂ C₄₃H₄₅NO₃S₃ +21.4, 50.3 182-4 720 c = 0.73, CH₂Cl₂ *: purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 66 ¹H-NMR data of A29~32 (δ ppm in CDCl₃) No 2″H 8″H 5″H 2′H

1′H 6H 4H 3H 5H A29 8.91 s 8.12 s 7.57 s 7.55-7.53(m, 2H), 7.43-7.40(m, 3H)  6.29, dd, 5.32 m 4.34-4.33 m 2.75-2.63 m 2.03-1.80 m 7.35-7.27(m, 6H), 7.14-7.10(m, 3H), J = 16.0, 6.0 6.85-6.83(m, 2H) A30 8.91 s 7.96 s 7.50 s 7.57-5.73(m, 2H), 7.38-7.33(m, 3H), 6.29, dd, 5.38-5.33 m 4.41-4.39 m 2.79-2.62 m 2.09-1.84 m 7.16-7.12(m, 2H), 7.05-7.00(m, 2H), J = 16.0, 6.0 6.87-6.80(m, 4H) A31 8.91 s 8.19 s 7.61 s 7.34-7.28(m, 2H), 7.21-6.83(m, 8H), 6.28, dd, 5.33-5.29 m 4.33-4.31 m 2.75-2.58 m 2.03-1.80 m 6.64-6.61(m, 1H), J = 16.0, 6.0 6.46-6.38(m, 2H), 3.79(s, 3H), 3.73(s, 3H), 3.67(s, 3H) A32 8.88 s 8.04 s 7.54-7.49(m, 3H), 7.37-7.26(m, 5H), 6.27, dd, 5.34-5.29 m 4.36-4.34 m 2.76-2.59 m 2.04-1.82 m 7.20(d, 2H, J = 8.0), 6.79(d, 2H, J = 8.0), J = 16.4, 6.0 6.75(d, 2H, J = 8.4), 2.98-2.91(m, 2H), 2.84-2.81(m, 1H), 1.31-1.26(m, 12H), 1.20(d, 6H, J = 7.2)

TABLE 67 (4R,6S)-6-[(E)-2-(6-fluoro-4,7,8-trisubstituted thiophenylquinoline-3-yl)-ethenyl]-3,4,5,6- tetrahydro-4-hydroxy-2H-pyran-2-one(A33~36)

MS Yield* Mp EI⁺ No R Formula [α]_(D) (%) (° C.) (M + 1) A33 H C₃₄H₂₆FNO₃S₃ +15.4, 65.7 138-9 612 c = 0.9, CH₂Cl₂ A34 p-F C₃₄H₂₃F₄NO₃S₃ +14.3, 52.4 194-6 665 c = 1, CH₂Cl₂ A35 m-OCH₃ C₃₇H₃₂FNO₆S₃ +17.9, 41.4 oil 702 c = 0.94, CH₂Cl₂ A36 p- C₄₃H₄₄FNO₃S₃ +16.6, 69.1 156-8 738 CH(CH₃)₂ c = 1, CH₂Cl₂ *: purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 68 ¹H-NMR data of A33~36 (δ ppm in CDCl₃) No 2″H 5″H 2′H

1′H 6H 4H 3H 5H A33 9.10 s 8.19, d, 7.32, dd, 7.22-7.04(m, 15H) 6.33, dd, 5.34-5.29 m 4.34-4.30 m 2.74-2.59 m 2.04-1.74 m J = 10.8 J = 16.2, 1.2 J = 16.4, 5.6 A34 9.11 s 8.20, d, 7.32, dd, 7.13-7.05(m, 3H), 6.81-6.58(m, 9H), 6.34, dd, 5.34-5.29 m 4.34-4.32 m 2.76-2.60 m 2.02-1.77 m J = 10.4 J = 16.4, 1.2 3.71-3.69(m, 9H) J= 16.0, 6.0 A35 9.09 s 8.16, d, 7.33, dd, 7.27-7.20(m, 4H), 7.09-7.06(m, 2H), 7.34, dd, 5.37-5.32 m 4.39-4.38 m 2.78-2.63 m 2.06-1.77 m J = 10.4 J = 16.0, 1.2 6.95-6.87(m, 6H) J = 16.4, 5.6 A36 9.11 s 8.17, d, 7.34, d, 7.14(t, 4H, J = 8.4), 7.08-7.02(m, 6H), 6.33, dd, 5.35-5.32 m 4.35-4.33 m 2.80-2.64 m 1.99-1.79 m J = 10.8 J = 16.4 6.98(d, 2H, J = 8.0) J = 16.0, 5.6 2.85-2.80(m, 3H), 1.20-1.18(m, 18H)

TABLE 69 (4R,6S)-6-[(E)-2-(4,6,7,8-tetrasubstituted thiophenylquinoline-3-yl)-ethenyl]-3,4,5,6- tetrahydro-4-hydroxy-2H-pyran-2-one(A37~40)

MS Yield* Mp EI⁺ No R Formula [α]_(D) (%) (° C.) (M + 1) A37 H C₄₀H₃₁NO₃S₄ +31.1, 69.6 200- 702 c = 0.92, 3 THF A38 p-F C₄₀H₂₇F₄NO₃S₄ +25.5, 75.5 218- 774 c = 1, 20  THF A39 m-OCH₃ C₄₄H₃₉NO₇S₄ +28.2, 80.0 oil 822 c = 1, CH₂Cl₂ A40 p- C₅₂H₅₅NO₃S₄ +21.9, 81.5 162- 870 CH(CH₃)₂ c = 1, 4 acetone *: purified by silica gel chromatography (petroleum ether-EtOAc)

TABLE 70 ¹H-NMR data of A37~40 (δ ppm in CDCl₃) No 2″H 5″H 2′H

1′H 6H 4H 3H 5H A37 8.98 s 7.87 s 7.43-7.25(m, 6H), 7.19-7.04(m, 13H), 6.30, dd, 5.33-5.29 m 4.35-4.34 m 2.75-2.59 m 2.03-1.79 m 6.74-6.72(m, 2H) J = 16.4, 6.0 A38 9.17 s 7.73 s 7.51-7.48(m, 2H), 7.33-7.27(m, 2H), 7.23-7.17(m, 3H), 5.31-5.23 m 5.14 s 2.71-2.42 m 1.94-1.75 m 7.14-6.97(m, 8H), 6.84-6.75(m, 3H) A39 9.00 s 7.95 s 7.32(dd, J = 16.4, 1.2) 7.26-7.22(m, 2H), 5.32 s 4.35-4.33 m 2.75-2.63 m 2.03-1.83 m 7.11-6.94(m, 6H), 6.74-6.57(m, 6H),  6.34-6.27(m, 3H), 3.72-3.66(m, 12H) A40 8.97 s 7.84 s 7.37-7.31(m, 3H), 7.22(d, 2H, J = 8.0), 6.29, dd, 5.31 s 4.35 s 2.75-2.59 m 2.02-1.79 m 7.13(d, 2H, J = 7.2), 7.06-6.95(m, 8H), J = 16.0, 5.6 6.66(d, 2H, J = 8.0), 2.97-2.94(m, 1H), 2.85-2.77(m, 3H), 1.29-1.16(m, 24H)

TABLE 71 In vitro inhibition on HMG CoA reductase of some quinoline compounds A (IC₅₀) No IC₅₀(Mm) rosuvastatin 9.03 atorvastatin 13.22 Fluvastatin 21.21 A16 3.21 A23 3.64 A40 4.35 A21 4.41 A14 7.93 A11 9.24 A24 10.60 A13 10.67 A34 11.94 A4  12.65 A32 14.15 A31 15.37 A20 15.75 A2  18.56 A12 22.05 A29 32.55 A22 38.93 A27 49.67 A35 74.55 

1. A quinoline compound of formula A or a stereoisomer thereof,

Wherein R₁, R₂ and R₃ are independently selected from the groups consisting of hydrogen, halogen, the group shown in formula H,

Wherein R is selected from the group consisting of hydrogen, halogen, C1˜4 alkyl or C1˜4 alkoxy.
 2. The compound according to claim 1, wherein halogen is F or Cl.
 3. The compound according to claim 1, wherein R is methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, or isopropoxy.
 4. The quinoline compound or stereoisomer according to claim 1, selected from: (4R,6S)-6-[(E)-2-(6,7,8-trifluoro-4-(4-isopropylthiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one; (4R,6S)-6-[(E)-2-(6-fluoro-4,7-di-(3-methoxythiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one; (4R,6S)-6-[(E)-2-(4,6,7,8-tetra-(3-methoxythiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one; (4R,6S)-6-[(E)-2-(6-fluoro-4,7-di-(thiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one; (4R,6S)-6-[(E)-2-(6,7,8-trifluoro-4-(4-fluorothiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one; (4R,6S)-6-[(E)-2-(7-chloro-6-fluoro-4-(3-methoxythiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one; (4R,6S)-6-[(E)-2-(6-fluoro-4,7-di-(4-isopropylthiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one; (4R,6S)-6-[(E)-2-(6,7,8-trifluoro-4-thiophenylquinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one; (4R,6S)-6-[(E)-2-(6-fluoro-4,7,8-tri-(4-fluorothiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one; or (4R,6S)-6-[(E)-2-(4-(4-isopropylthiophenyl)quinoline-3-yl)-ethenyl]-3,4,5,6-tetrahydro-4-hydroxy-2H-pyran-2-one.
 5. A method of preparation of the quinoline compound or stereoisomer according to claim 1, wherein compound D reacts under acid condition.
 6. The method of the preparation according to claim 5, wherein the acid is CF₃COOH, CH₃COOH or HCl.
 7. The method of the preparation according to claim 5, wherein the volume percentage of acid in solvent is 5-40%.
 8. The method of the preparation according to claim 7, wherein the volume percentage of acid in solvent is 20%.
 9. The method according to claim 5, wherein the temperature is 0° C.˜80° C.
 10. The method according to claim 9, wherein the temperature is 25° C.
 11. The method according to claim 5, wherein the reaction time is between 1˜8 hours.
 12. The method according to claim 5, wherein the solvent is selected from one or more of the following: THF, t-BuOMe, CH₂Cl₂, CHCl₃, and toluene.
 13. A method of inhibiting HMG CA reductase or treating diseases resulting from hyperlipemia, which comprise administering an effective amount of the compound or stereoisomer according to claim
 1. 